WO2023242597A1 - Molécules bifonctionnelles pour la dégradation ciblée de protéines - Google Patents

Molécules bifonctionnelles pour la dégradation ciblée de protéines Download PDF

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WO2023242597A1
WO2023242597A1 PCT/GB2023/051592 GB2023051592W WO2023242597A1 WO 2023242597 A1 WO2023242597 A1 WO 2023242597A1 GB 2023051592 W GB2023051592 W GB 2023051592W WO 2023242597 A1 WO2023242597 A1 WO 2023242597A1
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substituted
alkyl
heteroaryl
heterocycloalkyl
aryl
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PCT/GB2023/051592
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English (en)
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Andrea TESTA
Callum Macgregor
Gregor MEIER
David MCGARRY
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Amphista Therapeutics Limited
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Priority claimed from GBGB2208866.0A external-priority patent/GB202208866D0/en
Priority claimed from GBGB2219270.2A external-priority patent/GB202219270D0/en
Application filed by Amphista Therapeutics Limited filed Critical Amphista Therapeutics Limited
Publication of WO2023242597A1 publication Critical patent/WO2023242597A1/fr

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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • TPD BACKGROUND Targeted Protein Degradation
  • TPD approaches offer a number of advantages over other drug modalities (e.g. small molecule inhibitors, antibodies & protein- based agents, antisense oligonucleotides and related knockdown approaches) including: potentiated pharmacology due to catalytic protein removal from within cells; ability to inhibit multiple functions of a specific drug target including e.g.
  • the UPS relies on a complex cascade of protein-protein interactions that enables the polypeptide ubiquitin to be covalently attached to the protein intended for removal.
  • the ubiquitin on the protein then acting as a marker or tag to the proteasome which then degrades and removes the protein from the cell.
  • the UPS can be repurposed to degrade specific proteins using bifunctional chemical molecules, commonly referred to as bifunctional degraders, as therapeutic agents. These molecules act by inducing the proximity of desired substrates with UPS proteins to initiate a cascade of events which ultimately leads to degradation, and removal of the protein from the cell by the proteasome.
  • Proteolysis targeting chimeras constitute one such class of bifunctional degraders, which induce proximity of target proteins to the UPS by recruitment of specific ubiquitin E3 ligases.
  • PROTACs are composed of two ligands joined by a linker - one ligand to engage a desired target protein and another ligand to recruit a ubiquitin E3 ligase.
  • the ubiquitin E3 ligases used most frequently in PROTACs are von Hippel-Lindau (VHL) and Cereblon (CRBN).
  • VHL von Hippel-Lindau
  • CRBN Cereblon
  • PROTACs recruiting VHL are typically based on hydroxyproline-containing ligands
  • PROTACs recruiting CRBN are typically characterised by the presence of a glutarimide moiety, such as thalidomide, pomalidomide and lenalidomide or close analogues to act as the warhead.
  • ligases including mdm2 and the IAP family have also shown utility in PROTAC design.
  • these approaches suffer from a range of limitations, which restrict their utility to treat a wide range of diseases.
  • limitations of current PROTAC approaches include: inability to efficiently degrade some targets; poor activity of PROTACs in many specific cells due to low and variable expression of E3 ligases and other proteins required for efficient degradation; chemical properties which make it more difficult to prepare degraders with suitable drug-like properties including good drug metabolism & pharmacokinetic profiles; and high susceptibility to induced resistance mechanisms in tumours.
  • bifunctional degrader molecules have been described in WO 2019/238886, WO 2019/238817, WO 2019/238816, and WO 2022/129925.
  • WO 2019/238886, WO 2019/238817, WO 2019/238816, and WO 2022/129925 have been described in WO 2019/238886, WO 2019/238817, WO 2019/238816, and WO 2022/129925.
  • SUMMARY The present disclosure is based on the identification of a novel class of bifunctional molecules that are useful in a targeted and/or selective degradation of a desired protein, e.g. a “target protein”.
  • the present disclosure provides bifunctional molecules, which facilitate proteasomal degradation of selected target protein(s) using a novel class of warhead.
  • the bifunctional molecules described herein comprise a general structure of: TBL – L – Z wherein TBL is a target protein binding ligand and L is a linker.
  • the moiety “Z” (a “warhead”) modulates, facilitates and/or promotes proteasomal degradation of the target protein and may, in some cases, be referred to as a modulator, facilitator and/or promoter of proteasomal degradation.
  • the TBL moiety of the bifunctional molecule binds to a target protein.
  • the moiety Z (which is joined or otherwise connected to the TBL via the linker) then modulates, facilitates and/or promotes the degradation of this target protein, e.g.
  • the bifunctional molecules described in the present disclosure may be considered to comprise: a target protein binding ligand (TBL) (i.e. a ligand capable of binding (e.g. specifically binding) to a target protein; a warhead or degradation tag (Z) (e.g. moiety Z which acts to modulate, facilitate and/or promote the degradation of this target protein) and a linker (e.g. a chemical linker) which conjugates, joins or connects TBL and Z.
  • TBL target protein binding ligand
  • Z warhead or degradation tag
  • linker e.g. a chemical linker
  • the Z moiety of the bifunctional molecules described herein does not bind to the ubiquitin E3 ligases typically relied on in the classical PROTAC approaches discussed above (such as CRBN and VHL). Accordingly, the bifunctional molecules described herein are believed to modulate, facilitate and/or promote proteasomal degradation via an alternative mechanism. Thus, the present class of bifunctional molecules may be useful against a wider range of diseases (including those that are resistant to many PROTAC degraders).
  • a bifunctional molecule comprising the general formula: TBL – L – Z wherein TBL is a target protein binding ligand; L is a linker; and Z comprises a structure according to formula (ZI): wherein: ring A 2 is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S; R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, –CH(substituted aryl)-, - CH
  • ring A 2 when ring A 2 is an optionally substituted 4- to 7- membered monocyclic N-heterocycloalkyl, ring A 2 is not fused to an aromatic ring.
  • ring A 2 when ring A 2 is an optionally substituted 7- to 12-membered bicyclic N- heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, the term ‘heterocycloalkyl’ is intended to take its standard meaning in the art to exclude any of the two or three rings within these systems being aromatic.
  • Z does not comprise, for example, a tetrahydroquinoline or other fused heterocycloalkyl/aryl or fused heterocycloalkyl/heteroaryl system.
  • the linker may be appended to moiety Z via the R 2 group.
  • the linker may be attached to moiety Z by way of a covalent bond between an atom on the linker and an atom contained in the ring system of the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl of the R 2 group.
  • the linker may be attached to moiety Z by way of a covalent bond to the nitrogen atom of NR y or the benzylic carbon atom of the -CH(aryl)- or –CH(substituted aryl)-, for example by way of a covalent bond to the benzylic carbon atom of the -CH(aryl)- or – CH(substituted aryl)-.
  • R 2 may be absent.
  • the linker may be appended to moiety Z by way of a covalent bond between an atom on the linker and an atom contained in the heterocyclic ring (e.g. ring A 2 ).
  • the linker may be attached at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • the linker may be bonded at any position on the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)- or –CH(substituted aryl)- of the R 2 group or may replace a hydrogen atom at any position on the heterocyclic ring shown, for example, in formula (ZI).
  • ring A 2 is an optionally substituted 4- to 7-membered monocyclic N- heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S, such as N and O.
  • ring A 2 is bicyclic or tricyclic, and unless otherwise stated, it may comprise rings that are joined by a bond, rings that are fused, a bridged ring and/or rings that are joined at a spiro centre.
  • ring A 2 When ring A 2 is bicyclic, it may be a bridged bicyclic ring (i.e. it may comprise two rings that share three or more atoms) or it may be a spirocyclic bicyclic ring (i.e. it may comprise two rings that share one atom, e.g. the two rings may be joined at a spiro centre).
  • ring A 2 When ring A 2 is a bridged bicyclic ring, it may be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • ring A 2 is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S. In some examples, ring A 2 is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally containing one additional ring atom selected from N. When ring A 2 is a spirocyclic bicyclic ring, it may be an optionally substituted 7- to 12- membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • ring A 2 is a 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • ring A 2 is bicyclic and comprises a first 5- to 7-membered ring and a second 3- to 7-membered ring.
  • ring A 2 may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, and optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • ring A 2 may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, and optionally containing one additional ring heteroatoms selected from N.
  • Z comprises a structure according to formula (ZIa): wherein: R 1 is absent (i.e.
  • m when m is 0) or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-5 cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl (e.g.
  • R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, –CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl)-; wherein R y is optionally substituted C 1-6 alkyl or H; R 3 is selected from C 1 -C 6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkyl heterocycloo
  • Z does not comprise, for example, a tetrahydroquinoline or other fused heterocycloalkyl/aryl or fused heterocycloalkyl/heteroaryl system.
  • n is 1, 2 or 3 (i.e. when 1, 2 or 3 X 4 groups are present)
  • an X 4 group adjacent to (or directly bonded to) the N of the heterocyclic ring shown in formula (ZIa) is CH 2 .
  • Z comprises a structure according to formula (ZIb): wherein: R 1 is absent (i.e.
  • m when m is 0) or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-5 cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl (e.g.
  • R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, –CH(substituted aryl)-, - CH(heteroaryl)- and –CH(substituted heteroaryl)-; wherein R y is optionally substituted C 1-6 alkyl or H; R 3 is selected from C 1 -C 6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkyl heterocycloo
  • Z comprises a structure according to formula (ZIb’): wherein: R 1 , R 3 , X 1 , X 2 , X 3 , X 4 , n, m and L are as defined above in respect of formula (ZIa) and (ZIb).
  • Z comprises a structure according to formula (ZIb’’): wherein: R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , n and L are as defined above in respect of formula (ZIa) and (ZIb).
  • an optionally substituted C 1-3 bridge may be formed by two R 1 groups or, in some cases, by one R 1 group and one R x group.
  • the C 1 - 3 bridge may be a C 1 - C 3 alkylene bridging group, such as methylene, ethylene or propylene.
  • the C 1 -C 3 bridge may be methylene or ethylene.
  • the C 1-3 bridge may comprise from one to three (e.g. one or two) substituents (selected from any suitable substituent as described herein).
  • the C 1 to C 3 alkylene bridging group may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • Z may comprise a structure according to formula (I): wherein R 1 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl; R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , -CH(aryl)-, –CH(substituted aryl)-, - CH(heteroaryl)- and -CH(substituted heteroaryl)-; wherein R y is H or C 1 to C 6 alkyl; R 3 is selected from C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X 1 is CH 2 ; X 2 and X 3
  • R 2 may be absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, – CH(substituted aryl)-, -CH(heteroaryl)- and -CH(substituted heteroaryl)-. In some examples, at least one of R 1 or R 2 is present.
  • R 2 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , - CH(aryl)-, –CH(substituted aryl)-, -CH(heteroaryl)- and -CH(substituted heteroaryl)-.
  • R 2 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, – CH(substituted aryl)-, -CH(heteroaryl)- and -CH(substituted heteroaryl)-.
  • R 1 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl.
  • At least one R 1 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-6 cycloalkyl or optionally substituted 5- to 7- membered N-heterocycloalkyl, optionally wherein the C 3-5 cycloalkyl or the 5-7-membered N- heterocycloalkyl are joined to ring A at a spiro centre.
  • both of R 1 and R 2 are present.
  • R 2 is present and at least one R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form a optionally substituted C 1-3 bridge, optionally substituted C 3-6 cycloalkyl or optionally substituted 5- to 7- membered N-heterocycloalkyl.
  • R 1 and/or R 2 may be covalently attached to the heterocyclic ring (e.g. ring A) at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • R 1 and/or R 2 may replace a hydrogen atom at any position on the heterocyclic core, e.g. that shown in formula (I).
  • both R 1 and R 2 are present, they may be covalently attached to the heterocyclic ring (e.g. ring A) at the same or different positions.
  • R 1 and R 2 may be covalently attached to the heterocyclic core by way of different carbon atoms.
  • R 1 and R 2 may be covalently attached to the heterocyclic core by way of the same carbon atom.
  • a double bond is present in Z.
  • the stereochemistry of this double bond may be either E or Z and this is indicated by the wavy line bond in formula (I) (and is similarly shown on the other formulae and structures disclosed herein).
  • the designation of this moiety as either E or Z may depend on the identity of the R 3 group.
  • Z may comprise a mixture of E and Z stereoisomers.
  • the present disclosure includes within its scope the use of each individual E and Z stereoisomers of any of the disclosed Z moieties according to formula (I) and any of the other formulae described herein (e.g. in a substantially stereopure form), as well as the use of mixtures of these E and Z isomers.
  • the stereochemistry of the double bond and the moieties bound to it is Z, i.e. the Z stereoisomer.
  • the stereochemistry of the double bond and the moieties bound to it is E, i.e. the E stereoisomer.
  • the present disclosure includes within its scope the use of all stereoisomeric forms, or the use of a mixture of stereoisomers of the bifunctional molecules,
  • the bifunctional molecule comprises one or more chiral centres
  • the present disclosure encompasses each individual enantiomer of the bifunctional molecule as well as mixtures of enantiomers including racemic mixtures of such enantiomers.
  • the bifunctional molecule comprises two or more chiral centres
  • the present disclosure encompasses each individual diastereomer of the bifunctional molecule, as well as mixtures of the various diastereomers.
  • the various structures shown herein encompass all isomeric (e.g.
  • enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure embraces the R and S configurations for each asymmetric centre, and Z and E double bond isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are to be understood to be within the scope of the present disclosure. Additionally, unless otherwise stated, where present, all tautomeric forms of the bifunctional molecules described herein are to be understood to be within the scope of the present disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • bifunctional molecules as described herein in which one or more hydrogen atoms have been replaced by deuterium or tritium, or in which one or more carbon atoms have been replaced by a 13 C- or 14 C-enriched carbon are to be understood to within the scope of the present disclosure. Such molecules may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • a bifunctional molecule as described herein may be substituted with one or more deuterium atoms.
  • references to “a bifunctional molecule” may further embrace a pharmaceutically acceptable salt thereof.
  • Z may be represented as formula (Ic’): wherein: R 1 is absent (i.e.
  • m is 0) or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms that is optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents; C 3 to C 8 cycloalkyl being optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substituents; C 1 to C 6 alkyl optionally substituted with one to three substituents; and/or wherein two R 1 groups combine to form a C 1-3 bridge optionally substituted with one to three substituents, C 3- 5 cycloalkyl optionally substituted with one to three substituents or 5- to 7-membered N- heterocycloal
  • Z may be represented as formula (Ic): wherein: R 1 is absent or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms that is optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents; C 3 to C 8 cycloalkyl; C 1 to C 6 alkyl optionally substituted with one to three substituents; R 2 is absent or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted with one to three substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms; heterocycl
  • Z may be represented as formula (Id’): wherein: R 1 is absent (i.e. when m is 0) or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O and S; C 3 to C 8 cycloalkyl; C 1 to C 6 alkyl and C 1 to C 6
  • R 2 is absent or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents each independently selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted with one to three substitu
  • Z may be represented as formula (Id): wherein: R 1 is absent or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; C 3 to C 8 cycloalkyl; C 1 to C 6 alkyl and C 1 to C 6 haloalkyl; R 2 is absent or is selected from the group consisting of: phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C
  • Z may be represented as formula (Ie’): wherein: R 1 is absent (i.e. when m is 0) or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms containing 1 or 2 heteroatoms each independently selected from N, O and S; C 3 to C 7 cycloalkyl; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; C 1 to C 6 alkyl and C 1 to C 6 haloalkyl; wherein the phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy; and/or wherein two R 1 groups combine to form a C 1-3 bridge, C 3-5 cycloalkyl or 5- to 7- membered N-heterocycloalky
  • R 2 is absent or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; -NR y ; –CH(phenyl)-; and –CH(heteroaryl) wherein the heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O and S; and further wherein the phenyl, heteroaryl, heterocycloalkyl, - CH(phenyl)- and –CH(heteroaryl) are each optionally substituted with one substituent selected from the group consisting of halo, C 1 to C
  • Z may be represented as formula (Ie): wherein: R 1 is absent or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms containing 1 or 2 heteroatoms each independently selected from N, O and S; C 3 to C 7 cycloalkyl; C 1 to C 6 alkyl and C 1 to C 6 haloalkyl; wherein the phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C 1 to C 3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy; R 2 is absent or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; -NR y ;
  • Z comprises a structure according to formula (ZII): wherein R 2 is absent or is as described in any one of the embodiments disclosed herein; R 3 is as described in any one of the embodiments disclosed herein; X 5 is CR b 2, NR b , O or a 5- to 7-membered heterocycloalkyl (e.g.
  • each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 1-3 bridge or optionally substituted C 3-5 cycloalkyl (optionally wherein the C 3-5 cycloalkyl is joined to the heterocyclic ring shown in formula (ZII) at a spiro centre); R b is H or optionally substituted C 1-3 alkyl; n1 is 0, 1, 2 or 3; m is 0, 1 or 2; and L shows the point of attachment of the linker.
  • Z comprises a structure according to any one of formulae (ZIIa) to (ZIIe):
  • R 2 is as described in any one of the embodiments disclosed herein;
  • R 3 is as described in any one of the embodiments disclosed herein;
  • each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl, and/or wherein two R 1 groups combine to form an optionally substituted C 3-5 cycloalkyl (optionally wherein the C 3-5 cycloalkyl is joined to the heterocyclic ring shown in formula (ZIIa) at a spiro centre);
  • X 5 is C(R b ) 2 , NR b or O;
  • R b is H or optionally substituted C 1-3 alkyl;
  • n1 is 0, 1, 2 or 3;
  • n’ is 1 or 2;
  • m is 0, 1
  • R 2 is as described in any one of the embodiments disclosed herein;
  • R 3 is as described in any one of the embodiments disclosed herein;
  • each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl;
  • X 5 is CH 2 , NR b or O;
  • R b is H or optionally substituted C 1-3 alkyl;
  • n1 is 0, 1 or 2;
  • n’ is 1 or 2;
  • m is 0, 1 or 2; and
  • L shows the point of attachment of the linker.
  • Z comprises a structure according to formula (ZIVa) to (ZIVj):
  • R 2 is absent or is as described in any one of the embodiments disclosed herein;
  • R 3 is as described in any one of the embodiments disclosed herein;
  • each R 1 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl;
  • n1 is 0, 1 or 2;
  • n’ is 1 or 2;
  • m is 0, 1 or 2; and L shows the point of attachment of the linker.
  • Z comprises a structure according to formula (If): 1 wherein R is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl; R 2 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)- and –CH(substituted aryl)-; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted C 1 to C 6 alkyl, substituted aryl, and substituted heteroaryl; and wherein at least one of R1 and R 2 is present; n is 0, 1, 2, or 3; and L shows the point of attachment of the linker.
  • R is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl
  • R 1 , R 2 and R 3 of formula (If) may be selected from those groups defined above, e.g. for any one or more of formulae (Ic’), (Ic), (Id’), (Id), (Ie’) or (Ie).
  • n may be 1, 2 or 3 and/or n1 may be 0, 1 or 2.
  • Z may be represented by formula (II): wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, –CH(substituted aryl)-, - CH(heteroaryl)- and –CH(substituted heteroaryl); R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a a heterocycloalkyl group; X 1 is CH 2 ; X 2 and X 3 are each independently CH 2 or O; with the proviso that none or only 1 of X 2 and X 3 is O; and n is 0, 1, 2 or 3; and L shows the point of attachment of the linker; and wherein Z is not: In those cases where R 1
  • Z may be represented by formula (IIb): wherein R 2 is selected from aryl substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; X 1 is CH 2 ; X 2 and X 3 are each independently CH2 or O; with the proviso that none or only 1 of X 2 and X 3 is O; n is 1 or 2; and L shows the point of attachment of the linker; and wherein Z is not:
  • Z may be represented by formula (IIc): wherein R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl
  • Z may be represented by formula (IId): wherein R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2; and L shows the point of attachment of the linker.
  • R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl
  • R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group
  • n is 1 or 2
  • L shows the point of attachment of the linker.
  • Z may comprise a structure according to formula (IIe): wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2; and L shows the point of attachment of the linker.
  • Z may comprise a structure according to formula (IIf): wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and L shows the point of attachment of the linker.
  • R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group
  • L shows the point of attachment of the linker.
  • Z may comprise a structure according to formula (III): wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 to C 6 alkyl; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and n is 0,1, 2 or 3; and L shows the point of attachment of the linker. In some examples, n may be 1 or 2.
  • Z may be represented by formula (IIIa): wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 to C 6 alkyl; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and L shows the point of attachment of the linker.
  • Z may be represented by formula (IIIb): wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 -C 6 alkyl; R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; and L shows the point of attachment of the linker.
  • bifunctional molecules of formula (IIIb) comprise at least two stereocentres and so exist in several diastereomeric (and enantiomeric) forms.
  • the groups R 1 and L may exist in a trans relationship (e.g. these groups are held and/or oriented on opposite sides of the heterocyclic core). In other examples, the groups R 1 and L may exist in a cis relationship (e.g. these groups are held and/or oriented on the same side of the heterocyclic core).
  • bifunctional molecules of formula (IIIb) may encompass at least the following diastereomeric forms:
  • Z may be represented by formula (IV): wherein R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; R 4 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; and n is 0, 1, 2 or 3; and L shows the point of attachment of the linker.
  • Z may comprise a structure according to formula (IVa): wherein R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; R 4 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; and L shows the point of attachment of the linker. In either of formula (IV) or (IVa), R 4 may be selected from aryl or substituted aryl. Representative examples of groups R 1 , R 2 , R 3 and R 4 are now provided below which are applicable to any one or more of the formulae described herein (unless otherwise indicated).
  • R 1 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C 1 to C 6 alkyl, and substituted C 1 to C 6 alkyl.
  • R 1 is an optionally substituted aryl or an optionally substituted heteroaryl.
  • the aryl or heteroaryl may comprise one or more substituents selected from the group consisting of C 1 to C 6 alkyl (e.g. methyl), C 1 to C 6 alkoxy (e.g.
  • R 1 may be phenyl that is optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy.
  • R 1 may be heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents selected from the group consisting of halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; C 3 to C 8 cycloalkyl.
  • suitable R 1 groups include but are not limited to phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl.
  • R 1 is a cycloalkyl, such as a C 3 to C 7 cycloalkyl, or a C 3 to C 6 cycloalkyl.
  • R 1 is a C 1 to C 6 alkyl, such as a C 1 to C 3 alkyl that is optionally substituted with one to three substituents as defined herein.
  • suitable R 1 groups are illustrated below: In the structures shown above, the line intersected by a wavy line represents the covalent bond between the exemplary R 1 groups shown above and a carbon atom on the heterocycloalkyl core attached to the R 1 group in the parent structure of Z (as illustrated by the various formulae described herein).
  • two R 1 groups may combine to form a C 1-3 bridge or C 3-5 cycloalkyl.
  • two R 1 groups may combine to form a C 3- 5 cycloalkyl.
  • the C 3-5 cycloalkyl may be joined to the heterocyclic ring of the parent structure at a spiro centre.
  • R 2 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, –CH(substituted aryl)-, -CH(heteroaryl) and –CH(substituted heteroaryl); wherein R y is optionally substituted C 1-6 alkyl (such as methyl) or H
  • R 2 is present in Z (and/or the bifunctional molecules described herein) as a divalent group.
  • R 2 is selected from optionally substituted aryl and optionally substituted heteroaryl
  • R 2 may be selected from aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted with one to three substituents; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted with one to three substituents.
  • R 2 may be selected from phenyl optionally substituted with one to three substituents selected from H, C 1 to C 6 alkyl, halo, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 or 2 N atoms, the heteroaryl being optionally substituted with one to three substituents selected from C 1 -C 6 alkyl (e.g. C 1 to C 3 alkyl), halo (e.g. F), C 1 -C 6 haloalkyl (e.g. C 1 to C 3 haloalkyl) and C 1 to C 6 alkoxy (e.g. C 1 to C 3 alkoxy).
  • C 1 -C 6 alkyl e.g. C 1 to C 3 alkyl
  • halo e.g. F
  • C 1 -C 6 haloalkyl e.g. C 1 to C 3 haloalkyl
  • suitable examples of R 2 include (but are not limited to) optionally substituted phenyl, and optionally substituted pyrazolyl.
  • the heterocycloalkyl may have 3 to 10 ring atoms and contain 1 to 3 heteroatoms each independently selected from N, O and S, and the heterocycloalkyl may be optionally substituted with one to three substituents.
  • the heterocycloalkyl may have 5 to 8 ring atoms (e.g.6 ring atoms) and may contain 1 or 2 N atoms.
  • suitable examples include (but are not limited to) optionally substituted piperidinyl, and optionally substituted piperazinyl. Further examples of suitable R 2 groups are shown below:
  • R 6 may be selected from H, C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy. In some examples, R 6 may be selected from H and C 1 -C 6 alkyl.
  • the line intersected by a wavy line represents the covalent bond between the exemplary R 2 groups shown above and a carbon atom on the heterocycloalkyl core attached to the R 2 group in the parent structure of Z (as illustrated by the various formulae described herein).
  • R 3 is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted C 1 to C 6 alkyl, substituted aryl, and substituted heteroaryl.
  • R 3 may be selected from the group consisting of: C 1 to C 6 alkyl optionally substituted with a heterocycloalkyl group having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; aryl having 6 to 10 carbon ring atoms; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the aryl and the heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • aryl and heteroaryl may be optionally substituted with one or two substituents selected from halo (e.g. F) and C 1 to C 3 alkyl (e.g. methyl).
  • suitable R 3 groups include, but are not limited to, thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, oxetanyl, cyclobutanyl, cyclopropanyl, tert-butyl, imidazolyl, oxazolyl, thiophenyl, imidazo(1,2-a)pyridinyl, N-C 1 to C 6 alkylenemorpholine, and 4,5,6,7-tetrahydro-1,3-benzothiazolyl, such as thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, iso
  • R 3 groups may be substituted, such as substituted thiazolyl, substituted pyridinyl, substituted benzothiazolyl, substituted phenyl, substituted pyrazolyl, substituted isoxazolyl, substituted isothiazolyl, substituted tetrahydropyranyl, substituted tetrahydrofuranyl, substituted oxetanyl, substituted cyclobutanyl, substituted cyclopropanyl and substituted tert-butyl.
  • R3 is a substituted heteroaryl or aryl group, there may be one or more substituents on the aromatic ring e.g. it may be mono-, di- or tri-substituted.
  • R 3 is optionally substituted pyrazolyl or imidazolyl
  • a nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted with C 1 to C 6 alkyl, such as methyl.
  • suitable R 3 groups include, but are not limited to, optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted oxazoyl, optionally substituted isoxazolyl, tert-butyl, C 1 -C 6 alkyl comprising a morpholino substituent, optionally substituted benzothiazolyl and optionally substituted pyridinyl.
  • R 3 is a substituted aryl or heteroaryl group, there may be one or more substituents on the aromatic ring e.g. it may be mono-, di- or tri-substituted. Further examples of suitable R 3 groups are shown below:
  • dotted line on the structures indicates the position that each of the respective R 3 groups may be joined to the structure shown in the formulae described herein.
  • the R 3 group may be connected to the structure shown in formulae by a covalent bond to an atom at any position on the aromatic ring (provided that it has the correct valency and/or is chemically suitable).
  • a hydrogen at any position on the R 3 group may be replaced with a bond to the parent structures as shown in the formulae described herein.
  • R 5 may be any substituent as described herein or may be absent. In some examples, R 5 may be selected from halo (e.g.
  • n may be 0 to 5, such as 0 to 4, 0 to 3, or 0 to 2). Where more than one substituent is present, each substituent may be independently selected from the R 5 groups noted above.
  • R 6 may be C 1 to C 6 alkyl, such as methyl.
  • G may be selected from CH 2 , O and NH.
  • Q may be C 1 to C6 alkylene such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (- C(CH 3 ) 2 CH 2 -).
  • R 3 is selected from the group consisting of:
  • R 5 may be selected from C 1 to C 6 alkyl (e.g. methyl) and halo (e.g. F).
  • halo e.g. F
  • R 5 may be appended to the aryl or heteroaryl ring at any position (provided that it has the correct valency and/or is chemically suitable).
  • the line intersected by a wavy line represents the covalent bond between the exemplary R 3 groups shown above and the carbon atom of the parent structure of Z (as illustrated by the various formulae described herein).
  • this covalent bond (as illustrated in the various formulae described herein) may be formed at any position on the aromatic ring (provided that it has the correct valency and/or is chemically suitable).
  • a hydrogen at any position on the R 3 groups shown above may be replaced with a bond to the structure shown in formula (I).
  • a suitable R 3 group may be selected from the following:
  • R 3 group may be selected from the following:
  • a suitable R 3 group may be selected from the following:
  • R 4 may be selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl.
  • R 4 may be selected from aryl having 6 to 10 carbon ring atoms; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the aryl and the heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • R 4 may be an optionally substituted phenyl.
  • a suitable R 4 group may be selected from the following: R 7 may be any substituent as described herein or may be absent.
  • R 7 may be selected from C 1 to C 6 alkyl, halo, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy.
  • R 6 may be C 1 to C 6 alkyl or C 1 to C 3 alkyl (e.g. methyl).
  • R 7 may be covalently bonded to the aryl or heteroaryl ring at any position (provided that it has the correct valency and/or is chemically suitable).
  • representative examples of Z are illustrated below:
  • R 3 may be selected from any of those R 3 groups disclosed herein. In some cases, in the exemplary structures shown above, R 3 may be selected from the group consisting of:
  • Z is not (or does not comprise) a structure selected from one or more of the following: In some examples, Z is not (or does not comprise) the following structure: wherein R 2’ is selected from H and C 1 to C 6 alkyl; R 3’ is selected from C 1 to C 6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C 1 to C 6 alkyl is substituted with a heterocycloalkyl group; m is 3, 4 or 5; and L shows the point of attachment of the linker.
  • the bifunctional molecule is not:
  • Z may be represented as shown in formula (ZV) or (V): w herein ring A2 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , n and L are as defined in any one of the embodiments disclosed above.
  • Such compounds may be useful in a synthesis of the described bifunctional molecules, e.g. via a modular approach, wherein each of moieties TBL, Z and L are provided as separate building blocks.
  • L and Z may be joined to provide the compounds L-Z as described above (which may then be further reacted to join to an appropriate TBL moiety).
  • Intermediate/fragment As described above, structures comprising a Z moiety as described herein may find particular utility in targeted protein degradation. As such, intermediates comprising such Z moieties may have value in providing useful intermediates for the synthesis of bifunctional molecules for use in targeted protein degradation.
  • G is attached to the disclosed structures by way of a covalent bond
  • a compound comprising the Z moiety according to formula (VI) or (VIa): wherein ring A 2 , R 1 , R 2 , R 3 , n, X 1 , X 2 and X 3 are as defined in any one of the embodiments disclosed above.
  • G is appended to the heterocyclic core either directly or via the R 2 group.
  • G is attached to moiety Z by way of a covalent bond.
  • G may be attached (either directly or indirectly via R 2 ) at any position on the heterocyclic core (provided it has the correct valency and/or is chemically suitable).
  • G may replace a hydrogen atom at any position on the heterocyclic core.
  • the group G in formula (VI) or (VIa) is configured to enable attachment of the Z moiety to another chemical structure (such as a linker moiety or a linker-target protein binding ligand moiety) via formation of a new covalent bond. Following the formation of this new covalent bond, the group G may form part of the linker as defined herein.
  • G may comprise a functional group that is able to facilitate the formation of a new covalent bond between Z and another moiety, e.g. via formation of an amide, ester, thioester, keto, urethane, amine, or ether linkage, or via formation of a new carbon-carbon bond or new carbon-nitrogen bond.
  • G may be represented as shown below: wherein R G is absent or is a C 1 to C 6 alkyl, optionally substituted with one or more heteroatoms selected from N, O and S;
  • X G is a group that is selected from –CO 2 H, –(CO)-N-hydroxysuccinimide and –(CO)- pentafluorphenol esters, -CHO, -COR G1 , -OH, -NH 2 , -NHR G2 , halo (e.g.
  • O- leaving group such as -OTs (tosylate), OMs (mesylate), –OTf (triflate)
  • alkynyl azide, dienyl, aminoxy, tetrazinyl
  • E -cyclooctenyl, cyclooctynyl, norbornyl, boronic acid, boronate ester, alkylboranes or an organometallic group (e.g. organotin, zinc or other suitable reagent); and
  • R G1 and R G2 are each independently selected from C 1 to C 6 alkyl.
  • Linker (L) As described herein, the TBL is linked or coupled to moiety Z via a linker L.
  • the linker may be a chemical linker (e.g. a chemical linker moiety) and, for example, may be a covalent linker, by which is meant that the linker is coupled to Z and/or TBL by a covalent bond.
  • the linker acts to tether the target protein binding ligand and Z moieties to one another whilst also allowing both of these portions to bind to their respect targets and/or perform their intended function.
  • the linker may act to tether the target protein binding ligand to Z whilst also mitigating the possibility of the Z moiety disrupting, interfering with and/or inhibiting the binding of the target protein binding ligand to the target protein.
  • the linker may act to tether Z to the target protein binding ligand whilst also mitigating the possibility of the target protein binding ligand disrupting, interfering with and/or inhibiting the cellular interactions of Z (e.g.
  • the linker may function to facilitate targeted protein degradation by allowing each end of the bifunctional molecule to be available for binding (or another type of interaction) with various components of the cellular environment.
  • the linker may be configured to allow the target protein binding ligand to bind to the target protein without interference, disruption and/or inhibition from the Z moiety of the bifunctional molecule.
  • the linker may be configured to allow the Z moiety to interact with the various components in the cellular environment to modulate, facilitate and/or promote the proteasomal degradation of the target protein without interference, disruption and/or inhibition from the target protein binding ligand of the bifunctional molecule.
  • linker may depend upon the protein being targeted for degradation (the target protein) and/or the particular target protein binding ligand.
  • the linker may be selected to provide a particular length and/or flexibility, e.g. such that the target protein binding ligand and the Z moiety are held within a particular distance and/or geometry.
  • the length and/or flexibility of the linker may be varied dependent upon the structure and/or nature of the target protein binding ligand.
  • the TBL is connected directly to moiety Z by a covalent bond i.e, the linker is a covalent bond.
  • linker may comprise any number of atoms between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30 or between 1 and 10. In some cases the linker may comprise any number of atoms in a single linear chain of between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30 or between 1 and 10. In some examples of the disclosure, the linker may comprise any number of atoms in a single linear chain between 1 and 25, such as 25, or between 1 and 20, such as 3 and 20,, or between 1 and 18, such as 3 and 18.
  • the degree of flexibility of the linker may depend upon the number of rotatable bonds present in the linker.
  • a rotatable bond is defined as a single non-ring bond, bound to a nonterminal heavy atom (e.g. non-hydrogen atom).
  • an amide (C-N) bond is not considered rotatable because of the high rotational energy barrier.
  • the linkers may comprise one or more moieties selected from rings, double bonds and amides to reduce the flexibility of the linker.
  • the linker may comprise a greater number and/or proportion of single bonds (e.g. may predominantly comprise single non-ring bonds) to increase the flexibility of the linker. It may also be appreciated that the length of the linker may affect the degree of flexibility.
  • a shorter linker comprising fewer bonds may also reduce the flexibility of a linker.
  • the number of rotatable bonds present in the linker may be any number between 1 and 20, between 1 and 15, or between 1 and 10.
  • the number of rotatable bonds present in the linker may be any number between 2 and 9, between 2 and 8, or between 3 and 6.
  • the linker may comprise any number of atoms in a single linear chain between 10 and 20; and/or the number of rotatable bonds present in the linker may be any number between 2 and 8.
  • the structure of the linker (L) may be represented as follows: (L x ) q wherein each L x represents a subunit of L; and q is an integer greater than or equal to 1.
  • q may be any integer between 1 and 30, between 1 and 20 or between 1 and 5.
  • the linker comprises only one L x subunit and may be represented as L 1 .
  • the linker comprises two L x subunits that are covalently linked to one another and which may be represented as L 1 - L 2 .
  • the linker comprises three L x subunits that are covalently linked to one another and may be represented as L 1 -L 2 -L 3 .
  • L may comprise the following subunits L 1 , L 2 , L 3, L 4 ....up to L q .
  • R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 , and R L9 may be independently selected from H, halo, C 1 to C 6 alkyl, C 1 to C 6, haloalkyl, -OH, -O(C 1 to C 6 alkyl), -NH 2 , -NH(C 1 to C 6 alkyl), - NO 2 , -CN, -CONH 2 , -CONH(C 1 to C 6 alkyl), -CON(C 1 to C 6 alkyl) 2 , –S(O)OC 1 to C 6 alkyl, - C(O)OC 1 to C 6 alkyl, and -CO(C 1 to C 6 alkyl).
  • each of R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 , and R L9 may be independently selected from H and C 1 to C 6 alkyl.
  • the terms aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl groups are defined above.
  • the terminal L x subunits may link or couple the linker moiety to the TBL and Z moieties of the bifunctional molecule.
  • L 1 may link the linker to the TBL moiety and L q may link the linker to the Z moiety.
  • the one L x subunit e.g. L 1
  • the TBL and Z moieties may be covalently linked to L through any group which is appropriate and stable to the chemistry of the linker.
  • the linker may be covalently bonded to the TBL moiety via a carbon-carbon bond, keto, amino, amide, ester or ether linkage.
  • At least one of L x comprises a ring structure and is, for example, selected from a heterocycloalkyl, heteroaryl, cycloalkyl or aryl group.
  • the linker may be or comprise an alkyl linker comprising, a repeating subunit of –CH 2 -; where the number of repeats is from 1 to 50, for example, 1-50, 1-40, 1-30, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9.1-8, 1-7, 1-6, 1-5, 1-4, 1- 3 and 1-2.
  • the linker may be or comprise a polyalkylene glycol.
  • the linker may be or comprise a polyethylene glycol (PEG) comprising repeating subunits of ethylene glycol (C 2 H 4 O), for example, having from about 1-50 ethylene glycol subunits, for example where the number of repeats is from 1 to 100, for example, 1-50, 1-40, 1-30, 1-20, 1-191-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12 or 1-5 repeats.
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1a): wherein L 1A is absent or is selected from C 1 -C 6 alkylene (e.g.
  • C 1 -C 6 alkoxy e.g. - O(CH 2 )-, -O(CH 2 ) 2 - , -O(CH 2 ) 5 - , -CH 2 OCH 2 -
  • C 1 -C 6 alkylamino e.g. -NR L2A (CH 2 )-, - R L2A (CH 2 ) 2 - , -R L2A (CH 2 ) 5 - , -CH 2 R L2A CH 2 -
  • L 3A is selected from C 1 -C 3 alkylene (e.g.
  • C 1 -C 6 alkoxy e.g. -(CH 2 )O-, -(CH 2 ) 2 O- , - (CH 2 ) 5 O- , -CH 2 OCH 2 -
  • C 1 -C 6 alkylamino e.g. -(CH 2 )NR L2A -, -(CH 2 ) 2 NR L2A - , -(CH 2 ) 5 NR L2A - , -CH 2 NR L2A CH 2 -
  • R L2A is H or C 1 -C 6 alkyl (e.g. C 1- C 3 alkyl).
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1b): wherein L 1B is absent or is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. - O(CH 2 )-, -O(CH 2 ) 2 - , -O(CH 2 ) 5 - , -CH 2 OCH 2 -) and C 1 -C 6 alkylamino (e.g.
  • L2A is H or C 1 -C 6 alkyl (e.g.
  • L 5B is selected from C 1 -C 3 alkylene (e.g. ethylene), C 1 -C 6 alkoxy (e.g. -(CH 2 )O-, -(CH 2 ) 2 O- , - (CH 2 ) 5 O- , -CH 2 OCH 2 -) and C 1 -C 6 alkylamino (e.g. -(CH 2 )NR L2A -, -NR L2A (CH 2 ) 2 - , -(CH 2 ) 5 NR L2A - , -CH 2 NR L2A CH 2 -); wherein R L2A is H or C 1 -C 6 alkyl (e.g.
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1c): wherein L 1C is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S; L 2C is absent or is selected from C 1 -C 3 alkylene (e.g.
  • C 1 -C 6 alkoxy e.g. -(CH 2 )O-, - (CH 2 ) 2 O- , -(CH 2 ) 5 O- , -CH 2 OCH 2 -
  • C 1 -C 6 alkylamino e.g. -(CH 2 )NR L2A -, -(CH 2 ) 2 NR L2A - , - (CH 2 ) 5 NR L2A - , -CH 2 NR L2A CH 2 -
  • L 4C is selected from C 1 -C 3 alkylene (e.g.
  • R L2A is H or C 1 -C 6 alkyl (e.g.
  • R L2B is NR L2A ; or an N-linked optionally substituted 4- to 7-membered monocyclic N- heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • Linker (L) represented by the Formula L1c, L 1C and L 2C may be both absent.
  • R L2B in L 3C is an N-linked optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, optionally containing one or two additional ring heteroatoms selected from N, O and S, and L 3C is the terminal subunit of the linker attached, suitably covalently attached, to the TBL via R L2B .
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1d): wherein L 1D is absent or is selected from C 1 -C 3 alkylene, CO, C 1 -C 3 alkylene(N(C 1 -C 3 alkyl); L 2D is NR L2A or an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S; wherein R L2A is H or C 1 -C 6 alkyl (e.g.
  • L 3D is absent or is selected from C 1 -C 3 alkylene, –O-, -N(C 1 -C 3 alkyl)-, and CO.
  • the structure of the linker (L) may be, or comprise, a structure represented as shown in formula (L1e): wherein L 1E is C 1 -C 3 alkylene (e.g.
  • L 1A , L 1B , L 1C , L 1D , or L 1E is the terminal subunit of the linker structure attached (i.e.
  • L 3A , L 5B , L 4C , L 3D , L 3E is the terminal subunit of the linker structure attached (i.e. covalently bonded) to the TBL portion.
  • L 1A , L 1B or L 1D are absent, L 2A , L 2B or L 2D is directly attached (i.e. covalently bonded) to the W moiety.
  • L 3D is absent, L 2D is directly attached (i.e. covalently bonded) to the TBL portion.
  • linker portions such as L 1C , L 2D , L 2E examples of R L2B and, may be bicyclic or tricyclic, and unless otherwise stated, these moieties may comprise rings that are joined by a bond, rings that are fused, a bridged ring and/or rings that are joined at a spiro centre.
  • L 1C , L 2D , L 2E examples of R L2B may be bicyclic, it may be a bridged bicyclic ring (i.e. it may comprise two rings that share three or more atoms) or it may be a spirocyclic bicyclic ring (i.e. it may comprise two rings that share one atom, e.g.
  • L 1C , L 2D , L 2E examples of R L2B may be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a 7- or 8-membered bridged bicyclic N- heterocycloalkyl optionally containing one additional ring atom selected from N.
  • any one of L 1C , L 2D , L 2E , and examples of R L2B is a spirocyclic bicyclic ring, it may be an optionally substituted 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be bicyclic and comprises a first 5- to 7-membered ring and a second 3- to 7-membered ring.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, and optionally containing one or two additional ring heteroatoms selected from N, O and S.
  • L 1C , L 2D , L 2E , and examples of R L2B may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6- membered ring and a second 3- to 6-membered ring, and optionally containing one additional ring heteroatoms selected from N.
  • the structure of L 1C , L 2D , L 2E , and examples of R L2B may be any one selected from: Wherein L 1A and L 3A are as defined above; X 5 is C(R b )2, NR b or O; R b is H or optionally substituted C 1-3 alkyl; n1 is 0, 1, 2 or 3; n’ is 1 or 2; m is 0, 1 or 2
  • L 1C , L 2D , L 2E , and examples of R L2B is any one selected from:
  • L 1D is absent or is selected from C 1 -C 3 alkylene, –O-, -N(C 1 -C 3 alkyl)-, and CO.
  • L 3D is selected from C 1 -C 3 alkylene (e.g. methylene).
  • the linker (L) may be, or comprise, a structure represented as shown in formula (L1f): L 1F (L1f) wherein L 1F is selected from C 1 -C 3 alkylene, CO, and C 1 -C 3 alkylene(NR L1C ); wherein R L1C is H or C 1 -C 3 alkyl. In some examples, L 1F is selected from C 1 -C 3 alkylene (such as methylene). In any of the examples described herein, the linker is or comprises one or more of:
  • q1 is any integer between 1 and 20, or between 1 and 10 (e.g. between 1 and 5).
  • the linker is or comprises one or more of: wherein q2 is any integer between 1 and 20, or between 1 and 10 (e.g.3, 4, 5, 6 or 10).
  • the linker is or comprises one or more of:
  • linker is or comprises one or more of the following structures:
  • the linker is or comprises one or more of:
  • q3 is 1 to 8, such as 1 to 5, and q4 is 1 to 12, such as 1 to 10.
  • the linker is or comprises one or more of the following structures:
  • the structures shown above represent the entire linker.
  • the linker of the bifunctional molecule may comprise a plurality of the structures shown above.
  • the wavy lines are shown over the bond(s) that forms the link with the TBL and Z moieties respectively.
  • the bond(s) that forms the link with the TBL and/or Z moieties is (are) attached to a ring structure. On many of the structures described herein, this bond is shown as being attached at a particular position on the ring structure. However, the disclosure also encompasses joining or coupling to the TBL and Z moieties at any chemically suitable position on these ring structures.
  • Target protein may be any polypeptide or protein that the skilled practitioner wishes to selectively degrade in a cell or a mammal, e.g., a human or animal subject.
  • a “target protein” may be a protein or polypeptide that is selected by the skilled practitioner for increased proteolysis in a cell.
  • selected target protein may be any polypeptide or protein which has been selected to be targeted for protein degradation and/or increased proteolysis.
  • target protein does not include androgen receptor.
  • androgen receptor means a protein with the UniProtKB designation of P10275 (ANDR_HUMAN).
  • target protein does not include estrogen receptor.
  • esterogen receptor means a protein with the UniProtKB designation of P03372 (ESR1_HUMAN).
  • the bifunctional molecules disclosed herein may not be intended for use or may not be suitable for use in the targeted degradation of a target protein selected from an: (i) estrogen receptor; and (ii) androgen receptor. According to the disclosure, degradation of a target protein may occur when the target protein is subjected to and/or contacted with a bifunctional molecule as described herein, e.g.
  • Target proteins that may be subject to increased proteolysis and/or selective degradation when contacted to the bifunctional molecules of this disclosure (and the associated methods of using such molecules) include any proteins and polypeptides.
  • Target proteins include proteins and polypeptides having a biological function or activity such as structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transportation, and signal transduction functions and activities.
  • target proteins may include structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, epigenetic regulation, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioural proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including
  • Target proteins may include proteins from eukaryotes and prokaryotes, including humans, other animals, including domesticated animals, microbes, viruses, fungi and parasites, among numerous other targets for drug therapy.
  • target proteins may include, but are not limited to: (i) kinases (such as serine/threonine kinases and receptor tyrosine kinases); (ii) bromodomain-containing proteins (such as BET family proteins); (iii) epigenetic proteins (including histone or DNA methyl transferases, acetyl transferases, deacetylases and demethylases); (iv) transcription factors (including STAT3 and myc); (v) GTPases (including KRAS, NRAS, and HRAS); (vi) phosphatases; (vii) ubiquitin E3 ligases and deubiquitinase enzymes; (viii) nuclear hormone receptors (including, for example, thyroid hormone receptor, androgen receptor (AR) and estrogen
  • a target protein may also be selected from targets for human therapeutic drugs. These include proteins which may be used to restore function in numerous diseases, e.g. polygenic diseases, including for example, target proteins selected from B7.1 and B7, TNFR1, TNFR2, NADPH oxidase, BclI/Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo- oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine
  • Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channels.
  • Still further target proteins include Acetyl-CoA carboxylase, adenylosuccinate synthetase, SMARCA2; protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.
  • Target proteins may also be haloalkane dehalogenase enzymes.
  • bifunctional molecules according to the disclosure which contain chloroalkane peptide binding moieties (C1-C12 often about C2-C10 alkyl halo groups) may be used to inhibit and/or degrade haloalkane dehalogenase enzymes which are used in fusion proteins or related diagnostic proteins as described in PCT/US2012/063401 filed December 6, 2011 and published as WO 2012/078559 on June 14, 2012, the contents of which is incorporated by reference herein.
  • Target Protein Binding Ligand TBL
  • a “target protein binding ligand” refers to a ligand or moiety, which binds to a target protein, e.g. a selected target protein.
  • a target protein binding ligand may be any moiety, which selectively and/or specifically binds a target protein.
  • a bifunctional molecule according to this disclosure may comprise a target protein binding ligand, which binds to the target protein with sufficient binding affinity such that the target protein is more susceptible to degradation or proteolysis than if unbound by the bifunctional molecule.
  • the target protein binding ligand may bind to a target protein with a binding affinity of less than or equal to about 10 ⁇ M, less than or equal to about 1 ⁇ M, less than or equal to about 0.5 ⁇ M, or less than or equal to about 0.1 ⁇ M.
  • the ligand may bind to the target protein with a binding affinity of about 0.01 nM to about 10 ⁇ M, such as about 0.01 nM to about 8 ⁇ M, about 0.01 nM to about 5 ⁇ M, about 0.01 nM to about 3 ⁇ M.
  • binding affinity is a measure of the propensity of an object comprising two components bound together to separate (dissociate) into the two components.
  • the binding affinity is the measure of the propensity of the complex formed when the target protein binding ligand binds to the target protein to dissociate into separate components, i.e. the propensity of the target protein binding ligand to dissociate from the target protein.
  • the binding between the target protein and the target protein binding ligand may comprise one or more binding interactions, such as one or more of the group consisting of hydrogen bonding, dipole-dipole bonding, ion-dipole bonding, ion-induced dipole bonding, ionic bonding and covalent bonding.
  • the binding between the target protein and the target protein binding ligand may comprise a salt bridge (a combination of hydrogen and ionic bonding).
  • the target protein binding ligand moiety may not be a target protein binding ligand selected from: (i) an estrogen receptor binding ligand; and (ii) an androgen receptor binding ligand.
  • the target protein ligand comprised within the bifunctional molecules of the present disclosure is: (i) not a ligand that specifically binds to an estrogen receptor; and (ii) not a ligand that specifically binds to an androgen receptor.
  • the bifunctional molecules disclosed herein do not comprise a target protein binding ligand that binds to an estrogen receptor with a binding affinity of less than or equal to about 10 ⁇ M, or less than or equal to about 1 ⁇ M.
  • the bifunctional molecules disclosed herein may not comprise a target protein binding ligand that binds to an estrogen receptor with sufficient binding affinity such that the estrogen receptor is selectively degraded.
  • the bifunctional molecules as described herein were to be contacted with an estrogen receptor, the observed DC 50 values (for degradation of the estrogen receptor) would be greater than about 10000 nM, or greater than about 1000 nM.
  • the bifunctional molecules disclosed herein may not comprise a target protein binding ligand that binds to an androgen receptor with a binding affinity of less than or equal to about 10 ⁇ M, or less than or equal to about 1 ⁇ M. Additionally, in some examples, the bifunctional molecules disclosed herein may not comprise a target protein binding ligand that binds to an androgen receptor with sufficient binding affinity such that the androgen receptor is selectively degraded.
  • a target protein binding ligand may comprise or be derived from a small molecule (or analogue or fragment thereof) already known to act as a modulator, promoter and/or inhibitor of protein function (e.g. any small molecule known to bind to the target protein).
  • the target protein binding ligand may comprise or be derived from a small molecule that is known to inhibit activity of a given target protein.
  • Non-limiting examples of small molecules that can be comprised in the target protein binding ligand moiety of the bifunctional molecules described herein include: (i) binders to kinases (including serine/threonine kinases e.g. RAF, receptor tyrosine kinases and other classes), (ii) compounds binding to bromodomain-containing proteins (including BET family and others), (iii) epigenetic modulator compounds (including binders to histone or DNA methyl transferases, acetyl transferases, deacetylases & demethylases and others e.g.
  • kinases including serine/threonine kinases e.g. RAF, receptor tyrosine kinases and other classes
  • compounds binding to bromodomain-containing proteins including BET family and others
  • epigenetic modulator compounds including binders to histone or DNA methyl transferases, acetyl transferases, deacetylases & demethyl
  • HDAC histone deacetylase
  • lysine acetyl transferases such as P300 (EP300; adenoviral E1A binding protein of 300 kDa) and CBP (CREBBP; cyclic-AMP response element binding protein)
  • binders to transcription factors including STAT3, myc and others include binders to GTPases (including KRAS, NRAS, HRAS and others),
  • binders of phosphatases binders of ubiquitin E3 ligases (e.g.
  • binders of nuclear hormone receptors including, for example, thyroid receptor, androgen receptor (AR) and estrogen receptor (ER), although in some examples, as stated above, the target binding ligands do not comprise binders to androgen receptor and estrogen receptor
  • binders to aggregation-prone proteins including Beta-amyloid, tau, Htt, alpha-synuclein and polyQ- expanded proteins
  • binders to apoptotic & anti-apoptotic factors including Bcl2, Bcl-xl and Mcl-1
  • binders to polymerases including PARP & POLQ
  • small molecules that can be comprised in the target protein binding ligand moiety of the bifunctional molecules described herein include: (i) Hsp90 inhibitors, (ii) human lysine methyltransferase inhibitors, (iii) angiogenesis inhibitors, (iv) compounds targeting the aryl hydrocarbon receptor (AHR), (v) compounds targeting FKBP, (vi) compounds targeting HIV protease, (vii) compounds targeting HIV integrase, (viii) compounds targeting HCV protease, (ix) compounds targeting acyl-protein thioesterase-1 and -2 (APT1 and APT2) among numerous others.
  • the target protein binding ligand is derived from a BET inhibitor (e.g. the BET inhibitor IBET276).
  • the target protein binding ligand may comprise the following structure: wherein L shows the position of attachment of the linker and the dotted line on the structure above indicates that the linker may be joined to the target protein binding ligand via any position on the aromatic ring (e.g. in some examples, L may be present at the 4-position on this aromatic ring).
  • L shows the position of attachment of the linker and the dotted line on the structure above indicates that the linker may be joined to the target protein binding ligand via any position on the aromatic ring (e.g. in some examples, L may be present at the 4-position on this aromatic ring).
  • the present disclosure also encompasses joining or coupling to the linker at any chemically suitable position on this target protein binding ligand.
  • the target protein binding ligand may be derived from a BRD9 inhibitor, for example the target protein binding ligand may comprise the following structure: wherein L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • Kinase Inhibitors In other examples, the target protein binding ligand is derived from a kinase inhibitor. In such examples, the target protein binding ligand may comprise the following structure: wherein L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any chemically suitable position on this target protein binding ligand.
  • the target protein binding ligand may be derived from a kinase inhibitor, such as a CDK9 inhibitor, and may comprise the following structure: where L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • EGFR Alternatively, the target protein binding ligand may be derived from a kinase inhibitor such as a mutant EGFR inhibitor, and may have the following structure:
  • the target protein binding ligand may be represented by formula (EGFR1): wherein R 2A is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, heteroaryl, - O(C 1 -C 6 alkyl), and –NR a1 R b1 , wherein said C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl and heteroaryl are optionally further substituted with one to five R f1 groups; wherein each R a1 is independently H or C 1 -C 6 alkyl; wherein each R b1 is independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, -
  • the target protein binding ligand (TBL) represented in formula (EGFR1) may be appended to the linker L of the bifunctional molecule by way of a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L).
  • the linker may be attached at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • the linker of the bifunctional molecule may be covalently bonded to the R 2B or R 2C moiety of formula (EGFR1) at any position (provided that it has the correct valency and/or is chemically suitable).
  • R 2A is C 3 -C 7 heterocycloalkyl.
  • R 2A may be a C 3 -C 7 heterocycloalkyl comprising at least one N ring atom that is optionally substituted with one to three R f1 groups (as defined above).
  • R 2A may comprise the following structure: w he f1 rein R is halo; and wherein the wavy line bisects the bond that forms the attachment to the pyrimidinyl core of formula (EGFR1).
  • the target protein binding ligand may be represented by formula (EGFR2): wherein R A1 is selected from C 3 -C 7 heterocycloalkyl, heteroaryl, -O(C 1 -C 6 alkyl), or –NR a1 R b1 , wherein said C 3 -C 7 heterocycloalkyl and heteroaryl are optionally further substituted with one to five R f1 groups; R A2 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl; R A3 is absent or is selected from C 1 -C 6 alkyl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 cycloalkyl, -O(C 1 - C 6 alkyl), CN, –NR a1 R a1 , -NHC(O)(C 1 -C 3 alkyl),
  • X A1 is N.
  • R A1 is selected from C 3 -C 7 heterocycloalkyl, heteroaryl and NR a1 R b1 .
  • R A1 is selected from C 3 -C 7 heterocycloalkyl and heteroaryl, the C 3 -C 7 heterocycloalkyl and heteroaryl being optionally further substituted with one to five R f1 groups, wherein each R f1 is independently selected from sulfonyl, alkoxy and halo; R A3 is absent or is -C(O)NR a1 R b1 ; and R A2 is C 1 -C 6 alkyl.
  • R A1 is a C 5 -C 7 heterocycloalkyl containing at least one N heteroatom (e.g. piperidinyl) or is a heteroaryl containing at least one N heteroatom in the ring (e.g. pyrazolyl).
  • R f1 is selected from –SO 2 (C 3 -C 7 cycloalkyl) (e.g. – SO 2 (cyclopropyl)), halo (e.g. F), hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxy (e.g. methoxy).
  • R A2 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, such as C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • Representative examples of R A2 include, but are not limited to, isopropyl, sec-butyl and 1,1,1-trifluoropropan-2-yl.
  • R A3 is selected from C 1 -C 3 alkyl, C 3 -C 7 heterocycloalkyl, heteroaryl, –NR a1 R a1 and -C(O)NR a1 R b1 .
  • RA1 is selected from C3-C7heterocycloalkyl (e.g. piperidinyl) and heteroaryl (e.g. pyrazolyl), wherein said C 3 -C 7 heterocycloalkyl or heteroaryl is optionally further substituted with one to three R f1 groups selected from C 1 -C 6 alkyl, C 1 - C 6 alkoxy, hydroxy, halo, sulfonyl, and sulfonamide.
  • C3-C7heterocycloalkyl e.g. piperidinyl
  • heteroaryl e.g. pyrazolyl
  • the target protein binding ligand may be represented by formula (EGFR2a): wherein R A2 and R A3 are as defined in formula (2); and R f1b is selected from H and C 1 -C 6 alkyl (e.g. C 1 -C 3 alkyl); and R f1a is absent or is halo.
  • the target protein binding ligand (TBL) represented in formulae (EGFR2) and (EGFR2a) may be appended to the linker L of the bifunctional molecule by way of a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L).
  • the linker may be attached at any suitable position e.g.
  • the linker of the bifunctional molecule may be covalently bonded to the R A3 moiety of formula (EGFR2) or (EGFR2a) at any position (provided that it has the correct valency and/or is chemically suitable).
  • the linker of the bifunctional molecule may be covalently bonded to the heteroaryl ring as shown on formulae (EGFR2) and (EGFR2a).
  • the target protein binding ligand may be represented by formula (EGFR3): H wherein R A1 is selected from C 3 -C 7 heterocycloalkyl, heteroaryl, -O(C 1 -C 6 alkyl), or –NR a1 R b1 , wherein said C 3 -C 7 heterocycloalkyl and heteroaryl are optionally further substituted with one to five R f1 groups; R A2 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl; R A3’ is absent or is selected from C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, CN, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, -O(C 1 -C
  • each R A3’ is independently selected from C 1 -C 6 alkyl, halo, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, CN, amino, C 1 -C 6 alkylamino, -O(C 1 -C 6 haloalkyl), oxo, C 3 - C 7 cycloalkyl, C 3- C 7 heterocycloalkyl optionally substituted with C 1 -C 3 alkyl, C 1 -C 6 hydroxyalkyl, aryl and heteroaryl.
  • R A1 is selected from C 3 -C 7 heterocycloalkyl and heteroaryl, wherein said C 3 -C 7 heterocycloalkyl and heteroaryl are optionally further substituted with one to five R f1 groups as defined above.
  • R A1 may be selected from C5- C 7 heterocycloalkyl containing at least one N ring atom (e.g. piperidinyl) and a five- to six- membered heteroaryl containing one, two or three N ring atoms (e.g. pyrazolyl), both of which may optionally be further substituted with one to five R f1 groups as defined above.
  • the target protein binding ligand may be represented by formula (EGFR3a): wherein R A2 , R A3’ and n’ are as defined in formula (EGFR3); and R f1b is selected from H and C 1 -C 6 alkyl (e.g. C 1 -C 3 alkyl); and R f1a is absent or is halo.
  • R A2 may be C 1 -C 6 alkyl (such as isopropyl).
  • R A3’ may be selected from C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, C 3- C 7 heterocycloalkyl optionally substituted with C 1 -C 3 alkyl and -O(C 1 - C 6 haloalkyl).
  • n’ is 2 and a first R A3’ is -O(C 1 -C 6 haloalkyl) and a second R A3’ is C 3- C 7 heterocycloalkyl optionally substituted with C 1 -C 3 alkyl.
  • n’ is 1 and R A3’ is -O(C 1 -C 6 haloalkyl).
  • the target protein binding ligand (TBL) represented in formulae (EGFR3) and (EGFR3a) may be appended to the linker L of the bifunctional molecule by way of a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L).
  • the linker may be attached at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • the linker of the bifunctional molecule may be covalently bonded to the R A3’ moiety of formula (EGFR3) or (EGFR3a) at any position (provided that it has the correct valency and/or is chemically suitable).
  • R A3’ is absent
  • the linker of the bifunctional molecule may be covalently bonded to the heteroaryl ring as shown on formulae (EGFR3) and (EGFR3a).
  • target protein binding ligands that may be incorporated into the bifunctional molecules of the present disclosure are shown below:
  • L on the structures above represents the point of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • the linker may be attached to the target protein binding ligand at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • the TBL moiety may comprise one or more chiral centres.
  • the present disclosure encompasses each individual enantiomer of these TBL moieties as well as mixtures of enantiomers including racemic mixtures of such enantiomers.
  • the present disclosure encompasses each individual diastereomer of the TBL moiety, as well as mixtures of the various diastereomers.
  • the target protein binding ligand that may be incorporated into the bifunctional molecules of the present disclosure may be represented as: KRAS
  • the target protein binding ligand may be derived from a GTPase inhibitor, such as a KRAS G12C inhibitor.
  • the target protein binding ligand may have the following structure: where L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • the target protein binding ligand may be derived from a GTPase inhibitor, such as a KRAS G12D inhibitor.
  • the target protein binding ligand may have the following structure: where L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • the target protein binding ligand may be represented by formula (KRAS1): wherein: ring A 1 represents an optionally substituted saturated or unsaturated 5- to 10- membered N-containing ring which contains at least one further heteroatom selected from the group consisting of N, S and O and is optionally bridged; ring B 1 represents an optionally substituted moiety selected from the group consisting of a 5- to 6-membered unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and O, a 6- to 10-membered (e.g.6-membered) aromatic hydrocarbon ring, a C 3-6 cycloalkene ring and an 8-to 10-membered spiro ring, wherein the ring B 1
  • the linker may be attached the structure of formula (1) at any suitable position, for example where valency allows substitution or covalent addition of a linker moiety.
  • the linker is attached to the TBL via suitably substitution on Z 1 .
  • Z 1 is alkylaminocarbonyl or alkylaminoalkyl and m1 is 0 or 1.
  • m1 is 0.
  • the optional substituent of Y 1 of formula (KRAS1) may be one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C 1-4 alkyl, -S-C 1- 3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-3 cyanoalkyl , triazolyl, C 1-3 haloalkyl, -O- C 1-3 haloalkyl, -S-C 1-3 haloalkyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl, -CH 2 C(O)N(R C ) 2 , -C 3- 4 alkynyl(NR C ) 2 , -N(R C ) 2 , deuteroC 2-4 alkynyl, (C 1-3 alkoxy)haloC 1-3 alkyl-, and C 3-6 cycloalkyl, wherein said C 3-6 cyclo
  • the target protein binding ligand represented in formula (KRAS1) may be appended to the linker L of the bifunctional molecule by way of a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L).
  • the linker may be attached at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • the linker of the bifunctional molecule may be covalently bonded to the Z 1 moiety of formula (KRAS1) at any position (provided that it has the correct valency and/or is chemically suitable).
  • the target protein binding ligand may be represented by formula (KRAS2): wherein: ring A 1 represents an optionally substituted saturated or unsaturated 8- to 10-membered N- containing bridged ring which contains at least one further heteroatom selected from the group consisting of N, S and O; ring B 1 represents an optionally substituted moiety selected from the group consisting of a 5- to 6-membered unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and O, a 6-membered aromatic hydrocarbon ring, a C 3-6 cycloalkene ring and an 8-to 10-membered spiro ring, wherein the ring B 1 is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n1 is 0 or 1; X 1 is O or S; Y 1 is an optionally substituted moiety selected from the group consisting of a 6- to 10- membered aromatic hydrocarbyl
  • m1 is 0 or 1).
  • L or L-Z of the degrader is joined to the Z1 moiety.
  • Z 1 is alkylaminocarbonyl or alkylaminoalkyl.
  • Ring A 1 of formula (KRAS1) represents an optionally substituted saturated or unsaturated 5- to 10-membered N-containing ring containing at least one further heteroatom selected from the group consisting of N, S and O and is optionally bridged. Ring A 1 is often an optionally substituted, optionally bridged saturated 6- to 8-membered N-containing ring. Typically, A 1 contains two heteroatoms independently selected from N or O. Often, both heteroatoms are N.
  • a 1 is bridged, for example by a methylene, ethylene or propylene (typically a methylene or ethylene) bridge, wherein the bridge is optionally substituted, for example with one or more moieties selected from the group consisting of halo and hydroxy group.
  • ring A 1 is an optionally substituted piperazinyl ring, optionally bridged between two of the carbon atoms of the ring.
  • a 1 is an optionally substituted piperazinyl ring, optionally bridged between two of the carbon atoms of the ring wherein the piperazinyl ring is optionally substituted at nitrogen with hydroxy and is optionally substituted at carbon with one or more substituents selected from the group consisting of halo, alkoxycarbonyl, cyano,and hydroxyalkyl.
  • ring A 1 is of formula (KRAS1a): wherein: X 2 is NH, N(C 1-6 alkyl), NOH or O; n2’ is 1 or 2; R’ is the optional substituent as defined above; and n2 is 0 to 8 wherein when n2 is 2 to 4, two of R’ may join to form a bridge between two different carbon atoms of the ring.
  • R ’ is often a substituent independently selected from the group consisting of C 1-6alkyl, C1- 6 alkenyl, halo, alkoxycarbonyl, cyano or hydroxyalkyl (e.g. C 1-6 alkyl).
  • n2 is suitably 1 or 2.
  • a 1 may be any one moiety selected from the group consisting of: In some cases, A 1 is any one ring selected from the group consisting of:
  • a 1 may be Ring B 1 of formula (KRAS1)
  • Ring B 1 of formula (KRAS1) represents an optionally substituted moiety selected from the group consisting of a 5- to 6-membered unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and O, a 6-membered aromatic hydrocarbon ring, a C 3-6 cycloalkene and an 8-to 10-membered spiro ring, wherein the ring B 1 is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring.
  • B 1 is an optionally substituted moiety selected from the group consisting of a 5- to 6- membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N and O, a phenyl ring, and a C 5-6 cycloalkene. Often, B 1 is 6-membered. Sometimes, B 1 is aromatic.
  • B 1 is: (i) a 5- to 6-membered saturated or unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S, and O (such as N or O), (ii) a 6- to 10-membered aromatic hydrocarbon ring, (iii)C 3-6 cycloalkenyl or (iv) an 8- to 10-membered spiro ring; wherein B 1 is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; and wherein B 1 in the bicyclic ring may be substituted with one or more substituents selected from the group consisting of halo, C 1-6 alkyl, alkylcarbonyl and 4- to 6-membered saturated monocyclic heterocyclyl which contains one or more heteroatoms selected from N, S, and O.
  • B 1 is selected from the group consisting of benzene, piperidine, pyrrolidine, cyclohexane, cyclohexene, tetrahydro-2H-pyran, 3,4-dihydro-2H-pyran and spiro[2.5]octane; and is optionally substituted with one or more substituents selected from the group consisting of halo, C 1-6 alkyl, alkylcarbonyl and oxetanyl.
  • B 1 is selected from the group consisting of benzene, piperidine, pyrrolidine, tetrahydro-2H-pyran and 3,4-dihydro- 2H-pyran.
  • B 1 is pyrrolidine, n1 is 1 and X 1 is O or S, and when B 1 is not pyrrolidine, n1 is 0.
  • B 1 is an optionally substituted 6-membered N-heteroaromatic ring, such as an optionally substituted pyridine ring.
  • B 1 is any one ring selected from the group consisting of: wherein: n3 is 0 to 2; n3’ is 0 to 3; and R a is the optional substituent as defined above; and wherein in these structures, the wavy lines are shown over the bond(s) that forms the link with the parent structure (as shown in formulae (KRAS1), (KRAS2) and (KRAS3).
  • the optional substituent of B 1 is one or more moieties selected from the group consisting of halo (such as fluoro or chloro) and C 1-4 alkyl (such as methyl or ethyl). Often, the optional substituent of B 1 is one or more moieties selected from the group consisting of fluoro, chloro and ethyl. Often, B 1 is unsubstituted or substituted with fluoro. In some cases, B 1 is any one ring selected from the group consisting of:
  • B 1 may be Again, in any of the structures shown above, the wavy lines are shown over the bonds that forms the link with the parent structure (as shown in formulae (KRAS1), (KRAS2) and (KRAS3)).
  • Moiety L 1 -(CH 2 ) m1 -Z 1 of formula (KRAS1) L 1 is absent or is any one moiety selected from the group consisting of O, optionally substituted C 2-3 alkynylene and NR c, wherein R c is as defined above in formula (KRAS1) or (KRAS3).
  • m1 is 0 to 3. In some cases, L 1 is O and m1 is 1 or 2. Sometimes, L 1 is O and m is 1.
  • the linker of the degrader is joined to the Z 1 moiety at any position (provided that it has the correct valency and/or is chemically suitable).
  • Z 1 comprises an aromatic or heteroaromatic ring
  • the linker may replace a hydrogen atom at any position on the ring.
  • Each D is independently a C 1-4 alkylene optionally substituted with hydroxy, C 1-4 hydroxyalkyl or heteroaryl.
  • Each R C is independently hydrogen or C 1-3 alkyl.
  • Each R D is independently halo, hydroxy, C 1-3 hydroxyalkyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, cyano, -Q-phenyl, -Q-phenylSO 2 F, -NHC(O)phenyl, - NHC(O)phenylSO 2 F, C 1-3 alkyl substituted pyrazolyl, araC 1-3 alkyl-, tert- butyldimethylsilyloxyCH 2 - , -N(R C ) 2 , (C 1-3 alkoxy)C 1- 3alkyl-, (C1-3alkyl)C(O), oxo, (C1-3haloalkyl)C(O)-, -SO2F, (C1-3alkoxy)C1-3alkoxy, - CH 2 OC(O)N(R C ) 2 , -CH 2 NHC(O)OC 1-6 alkyl, -CH 2 NHC
  • Q is a bond or O.
  • Each R E is independently halogen, hydroxy, HC(O)-, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1- 4 hydroxyalkyl, or -N(R C ) 2 .
  • Z 1 is as defined in (i).
  • L 1 may be O or substituted or unsubstituted C 2-3 alkynyl; and Z 1 may be cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, C 3- 6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and O, an 8- to 10-membered partially unsaturated ring which contains at least one heteroatom selected from the group consisting of N, S, and O; wherein the ring in Z 1 may be substituted by halo, hydroxy, C 1-6 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1- 3 methoxyalkyl, a substituted or unsubstituted 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and O, and which may be substituted by C 1-3 alkyl, al
  • L 1 is O
  • m1 is 0 or 1
  • Z 1 is dimethylaminocarbonyl or dimethylaminomethyl.
  • L 1 is O
  • m1 is 0 or 1
  • Z 1 is a C 3-6 cycloalkyl, a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and O, an 8- to 10-membered partially saturated ring which contains at least one heteroatom selected from the group consisting of N, S, and O; wherein the ring in Z1 may be substituted with halo, hydroxy, C1-6alkyl, C1-3alkoxy, C 2-3 alkynyl, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl or C 1-6 alkyl which is substituted with a 5- to 6-member
  • Z 1 is: (i) cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline or 1,2,3,4-tetrahydroisoquinoline, and may be substituted with a halo, hydroxy, cyano, C 1-6 alkyl, or C 1-3 alkoxy; or (ii) alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalky or C 1-6 alkyl which is substituted with a 5- to 6-membered saturated ring which contains at least one heteroatom selected from the group consisting of N and O and which may be further substituted with a halo.
  • Z 1 is cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline, or 1,2,3,4- tetrahydroisoquinoline which may be substituted with a halo, hydroxy, C 1- 3alkoxy, methyl, ethyl, isopropanyl, ethylcalbonylmethyl, hydroxyethyl, dimethylamino, dimethylaminomethyl, methoxyethyl, cyanomethyl, morpholylmethyl, or 3- fluoropyrrolidinylmethyl.
  • Z 1 is as defined in (ii).
  • L 1 is O
  • m1 is 0
  • Z 1 is C 1-6 alkyl (such as methyl, ethyl, isopropyl or isobutyl) or -D-heterocyclyl optionally substituted with one or more R D (as defined above with respect to formulae (KRAS1) and (KRAS3)).
  • D is methylene and the heterocyclyl is selected from the group consisting of hexahydro-1H-pyrrolizinyl, hexahydro-3H-pyrrolizin-3-one, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazinyl, octahydroindolizinyl, hexahydropyrrolizine 4(1H)-oxide, azetidinyl, pyrrolidinyl, pyrrolidin-2-one, oxetanyl, piperidinyl, 1-azabicyclo[2.2.1]heptanyl, morpholinyl, oxa-5- azabicyclo[2.2.1]heptan-5-yl, thiopyranyl, 6-oxa-2- 2 ⁇ 2 -azaspiro[3.4]octanyl, 7-oxa-2 ⁇ 2 - azaspiro[3.5]nonanyl,
  • D is methylene and the heterocyclyl is hexahydro-1H-pyrrolizinyl, optionally substituted with one or more R D .
  • the heterocyclyl is hexahydro-1H-pyrrolizinyl substituted with one or more R D independently selected from the group consisting of halo (such as fluoro), hydroxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 alkoxy, phenyl or pyrazolyl.
  • the heterocyclyl is hexahydro-1H-pyrrolizinyl substituted with three R D groups, one of which is halo (such as fluoro), hydroxy, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkyl, C 1- 3 alkoxy, phenyl or pyrazoly, and two of which are independently C 1-3 alkyl.
  • the heterocyclyl is azetidinyl substituted with a C 1-3 alkyl.
  • the heterocyclyl is pyrrolidinyl substituted with any one moiety selected from the group consisting of hydroxalkyl, haloalkyl, C 1-3 alkyl, alkoxy, araC 1-3 alkyl, -Q- phenyl and - NHC(O)phenyl, and wherein the aryl portion of the araC 1-3 alkyl or the phenyl portion of the - Q-phenyl and -NHC(O)phenyl are each optionally substituted with one or more R D , such as SO 2 F.
  • the heterocyclyl may be pyrrolidinyl substituted with two groups, wherein the first is a C 1-3 alkyl and the second is a C 1-3 alkoxy or a halo. Sometimes, the heterocyclyl is pyrrolidin-2-one substituted with a C 1-3 alkyl. In some cases, the heterocyclyl is piperidinyl substituted with any one of the group consisting of acetyl, (C 1-3 alkoxy)C 1-3 alkoxy, or -C(O)CH 2 Cl.
  • L 1 is O, m1 is 0, D is ethylene or propylene and the heterocyclyl is morpholinyl or oxa- 5-azabicyclo[2.2.1]heptan-5-yl.
  • L 1 is O, m1 is 0 and Z 1 is -D-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R E .
  • D may be methylene or ethylene and the heteroaryl may be pyridyl, pyrazolyl, imidazolyl, triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, or pyrimidinyl, each optionally substituted with one or more R E .
  • R E may be one or more independently selected from the group consisting of halo, C 1-4 alkyl, - N(R C ) 2 , or C 1-4 alkoxy.
  • the heteroaryl may be pyrazolyl substituted with C 1-4 alkyl or -N(R C ) 2 .
  • the heteroaryl may be imidazolyl substituted with any one moiety selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 hydroxyalkyl.
  • the heteroaryl is triazolyl substituted with C 1-4 alkyl.
  • L 1 is O
  • m1 is 0
  • Z 1 is -D-aryl, wherein the aryl portion is optionally substituted with one or more R E (as defined above with respect to formulae (KRAS1) and (KRAS3)).
  • L 1 is O, m1 is 0 and Z 1 is -D-cycloalkyl, wherein the cycloalkyl portion is optionally substituted with one or more R E (as defined above with respect to formulae (KRAS1) and (KRAS3)).
  • R E as defined above with respect to formulae (KRAS1) and (KRAS3).
  • L 1 is O, m1 is 0 and Z 1 is -D-N(R C ) 2 .
  • D may be ethylene and each R C may be independently selected from C 1-3 alkyl.
  • D may be ethylene or propylene.
  • L 1 is O, m1 is 0 and Z 1 is -D-C 1-6 haloalkyl.
  • L 1 may be O, m1 may be 0 and Z 1 may be -D-OR C .
  • L 1 may be O, m1 may be 0 and Z 1 may be -D-(CH 2 OR C )(CH 2 ) n OR C .
  • L 1 may be O, m1 may be 0 and R 2 may be -D- NR C C(O)-aryl.
  • Y 1 is an optionally substituted moiety selected from the group consisting of a 6- to 10- membered aromatic hydrocarbyl ring and a 6-to 10-membered unsaturated monocyclic or bicyclic ring, which contains at least one heteroatom selected from the group consisting of N, S and O.
  • Y 1 may be an optionally substituted 6- to 10-membered aromatic hydrocarbyl ring, such as an optionally substituted moiety selected from the group consisting of naphthyl, phenyl, 1, 2,3,4- tetrahydronaphthalenyl and 2,3-dihydro-1H-indenyl.
  • Y 1 is a substituted naphthyl, for example a naphthyl substituted with one or more substituents selected from the group consisting of hydroxy, ethynyl, halo (such as chloro or fluoro), C 1- 4 alkyl and C 1-4 alkoxy.
  • substituents selected from the group consisting of hydroxy, ethynyl, halo (such as chloro or fluoro), C 1- 4 alkyl and C 1-4 alkoxy.
  • Y 1 is an 8- to 10-membered unsaturated bicyclic ring which contains at least one heteroatom selected from the group consisting of N and S, or a 6- to 10-membered aromatic hydrocarbon ring; wherein the ring may be substituted with one or substituents selected from the group consisting of halo, hydroxy, amino, C 1-6 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and 5- to 6-membered unsaturated monocyclic heterocyclyl which contains one or more heteroatoms selected from the group consisting of N, S and O.
  • Y 1 is selected from the group consisting of benzene, naphthalene, benzo[b]thiophene, thieno[3,2-b]pyridine, isoquinoline, indole, and indazole, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, amino, C 1-6 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and thiophenyl.
  • Y 1 is an optionally substituted heteroaryl such as an optionally substituted moiety selected from the group consisting of isoquinolinyl, indazolyl, or benzo[d][1,3]dioxolyl.
  • Y 1 may be isoquinolinyl substituted with a halo or C 2-4 alkynyl.
  • Y 1 may be indazolyl substituted with a chloro or a C 1-3 alkyl.
  • Y 1 may be benzo[d][1,3]dioxolyl substituted with two halo.
  • Y 1 is of formula (KRAS1b): wherein: X 3 is any one selected from the group consisting of CH, CR b and N; n4 is 0 to 4; and R b is the optional substituent, described above.
  • the wavy lines on formula (1b) is shown over the bond that forms the link with the parent structure (as shown in formula (1).
  • n4 is 2 or 1 (such as 2).
  • X 3 is CH or CR b .
  • R b may be any one or more substituents selected from the group consisting of hydroxy, C 2- 4 alkynyl (such as ethynyl), halo (such as chloro or fluoro), C 1-4 alkoxy (such as methoxy), C 1- 4 alkyl, C 2-4 haloalkynyl (such as haloethynyl), C 1-4 haloalkyl, C 2-4 alkenyl (such as ethenyl), C 2- 4haloalkenyl, C1-4haloalkoxy (such as halomethoxy), C3-4cycloalkyl (such as cyclopropyl), C1- 4alkenylol and amino.
  • R b may be any one or more substituents selected from the group consisting of hydroxy, C 2-4 alkynyl (such as ethynyl), halo (such as chloro or fluoro), C 1-4 alkoxy (such as methoxy), C 1-4 alkyl, C 2-4 haloalkynyl (such as haloethynyl) and C 1- 4 haloalkyl.
  • R b (or the optional substituent) is any one or more substituents selected from the group consisting of halo, cyano, hydroxy, C 1-4 alkyl, -S-C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 2-4 hydroxyalkynyl, C 1-3 cyanoalkyl, triazolyl, C 1-3 haloalkyl, -O-C 1-3 haloalkyl, -S-C 1- 3 haloalkyl, C 1-3 alkoxy, hydroxyC 1-3 alkyl, -CH 2 C(O)N(R 5 ) 2 , -C 3-4 alkynyl(NR 5 ) 2 , -N(R 5 ) 2 , deuteroC 2-4 alkynyl, (C 1-3 alkoxy)haloC 1-3 alkyl-, and C 3-6 cycloalkyl wherein said C 3-6 cycloalkyl is optional
  • a 1 is of the following formula: B 1 is benzene, piperidine, or pyrrolidine each of which are optionally substituted with a halo or C 1-6 alkyl; wherein when B 1 is pyrrolidine, n1 is 1 and X 1 is O, and when B 1 is not pyrrolidine, n1 is 0; Y 1 is naphthalenyl which may be substituted with a halo, hydroxy, C 1-6 alkyl, C 2-3 alkenyl, or C 2- 3 alkynyl; L 1 is O; m1 is 1; and Z 1 is cyclobutanyl, cyclopropanyl, piperidinyl, morpholinyl, piperazinyl, isoindolinyl, or 1,2,3,4- tetrahydroisoquinolinyl, each of which is optionally substituted with a halo, hydroxy, C 1-3 alkoxy, methyl, ethyl, isopropany
  • the target protein binding ligand may be derived from a CBP and/or p300 inhibitor.
  • the target protein binding ligand may have the following structure: where L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • the target protein binding ligand may be represented by formula (C1): wherein: the linker moiety of the bivalent compound is attached to R B or R A ; X A and X C are independently selected from C and N, with the proviso that at least one of X A and X C is C and only one or fewer of X A and X C is N; X B is selected from CR XB1 , O, and NR XB2 , wherein R XB1 is any one substituent selected from the group consisting of H, optionally substituted C 1-8 alkyl, and optionally substituted 3-10 membered carbocyclyl; and wherein R XB2 is absent or any one substituent selected from the group consisting of H, optionally substituted C 1-8 alkyl, and optionally substituted 3-10 membered carbocyclyl; A A is absent or is selected from the group consisting of, CR AA1 R AA2 , CO, O, S, SO, SO 2 ,
  • the target protein binding ligand represented in formula (C1) may be appended to the linker L of the bifunctional molecule by way of a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L).
  • the linker may be attached at any suitable position e.g. provided it has the correct valency and/or is chemically suitable.
  • the linker of the bifunctional molecule may be covalently bonded to TBL as shown in formula (C1) by way of the R A or R B groups.
  • the linker may be covalently bonded to an atom on either of the R A or R B groups of formula (C1) at any position (provided that it has the correct valency and/or is chemically suitable) (e.g. by replacing a hydrogen atom).
  • the linker is attached to R A .
  • the linker is attached to R B .
  • the linker is instead attached (e.g. covalently bonded) to A B .
  • the linker is instead attached (e.g. covalently bonded) to X C .
  • XA is C and X B and X C are each N, i.e. the compound is of formula (C2): wherein the linker moiety of the bivalent compound is attached to R B or R A and A A A B , R A , R B and R C are as defined above in respect of formula (C1).
  • a A -A B -R A moiety of formulae (C1 and C2) in some examples, the A A -A B -R A moiety is represented by formula (C3): wherein: A A and R A are as defined above for formula (C1); X 4 is selected from CR X41 and N, wherein R X41 is selected from hydrogen, halo, hydroxy, amino, cyano, nitro, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1- 6 alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and R AB4 is absent,
  • a A is absent.
  • a B -R A is represented by formulae (C4) or (C5): wherein R A is as defined above.
  • R A is as defined above.
  • a A is NR AA1 , wherein R AA1 is selected from the group consisting of hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 2-8 alkenyl, optionally substituted C 2- 8 alkynyl, optionally substituted C 1-8 alkoxyC 1-8 alkyl, optionally substituted C 1-8 alkylaminoC 1- 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R AA1 is selected from the group consisting of hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 2-8 alkenyl, optionally substituted C 2- 8 alkynyl, optionally substituted C 1-8 alkoxyC 1-8 alkyl, optionally substituted C 1-8 alky
  • R A is as defined above.
  • a A -A B -R A is represented by any one of formulae (C6), (C7) and (C8), wherein R A is as defined above for formula (C1).
  • R A is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.
  • R A is aromatic.
  • R A may be selected from optionally substituted aryl (such as phenyl) and optionally substituted heteroaryl (such as pyrazolyl or pyridinyl).
  • R A is an optionally substituted heteroaryl.
  • R A may be selected from optionally substituted pyrazolyl (such as N-methylpyrazolyl) and optionally substituted pyridinyl.
  • a A -A B -R A is represented by any one of formulae (C9) to (C12):
  • a A -A B -R A is represented by any one of formula (C9).
  • R B moiety of any one of formulae (C1) to (C12) As described above, R B is absent or is selected from the group consisting of R B1 O, R B1 S, R B1 NR B2 , R B1 OC(O), R B1 OC(O)O, R B1 OCONR B2 , R B1 C(O), R B1 C(O)O, R B1 CONR B2 , R B1 S(O), R B1 SO 2 , R B1 SO 2 NR B2 , R B1 NR B3 C(O)O, R B1 NR B3 C(O), R B1 NR B3 C(O)NR B2 , R B1 NR B3 S(O), R B1 N R B3 SO 2 , R B1 NR B3 SO 2 NR B2 , optionally substituted C 1-8 alkylene, optionally substituted C 2- 8 al
  • R B is connected to the “linker” moiety of the bifunctional molecule.
  • R B is selected from optionally substituted C 1-8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, o ptionally substituted aryl, and optionally substituted heteroaryl.
  • RB is optionally substituted 4-8 membered heterocyclyl.
  • R B is optionally substituted 4-8 membered N-heterocyclyl such as an optionally substituted 5-7 membered N-heterocyclyl.
  • R B is optionally substituted 6 membered N-heterocyclyl such as an optionally substituted piperidinyl.
  • R B is piperidinyl, wherein the piperidinyl is bonded to the linker via the nitrogen atom.
  • R C moiety of any one of formulae (C1) to (C12)
  • R C is selected from hydrogen, COR C1 , CO 2 R C1 , CONR C1 R C2 , SOR C1 , SO 2 R C1 , SO 2 NR C1 R C2 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R C1 and R C2 are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R C1 and R C2 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.
  • R C is selected from the group consisting of COR C1 and CONR C1 R C2 , wherein R C1 and R C2 are as defined above.
  • R C1 and R C2 are each independently selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl.
  • R C1 and R C2 may each independently be selected from hydrogen and unsubstituted C 1-6 alkyl (such as unsubstituted C 1-3 alkyl).
  • R C1 is a C 1-6 alkyl (such as a C 1- 3 alkyl, e.g. methyl) and R C2 is hydrogen.
  • R C is selected from COMe and CONHMe.
  • the target protein binding ligand may be derived from a polymerase inhibitor, such as a PARP1 inhibitor.
  • the target protein binding ligand may have the following structure:
  • the target protein binding ligand may be derived from a polymerase inhibitor, such as a POLQ inhibitor.
  • the target protein binding ligand may have the following structure: where L shows the position of attachment of the linker.
  • the target protein binding ligand may be derived from a deubiquitinase inhibitor, such as a USP1 inhibitor.
  • the target protein binding ligand may have the following structure:
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • Representative examples of possible target protein binding ligand moieties for each of the various classes of target protein binding ligands are described below.
  • SMARCA2/SMARCA4 In some instances, the target protein binding ligand may be derived from a SMARCA2 inhibitor.
  • the target protein binding ligand may have the structure of formula 1T: wherein the wavy line intersects the bond between the SMARCA2/SMARCA4 binder and the linker; and wherein: R 1T is hydrogen, halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, hydroxy, -COOR at , - CON(R at ) 2 , C 6 -C 10 aryl or C 5 -C 9 heteroaryl; wherein, the alkyl, alkenyl, alkoxy, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, amino, - COOR at and -OCOR at ; wherein each R at is independently selected from hydrogen and C 1 -C
  • R 1T is C 6 -C 10 aryl optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, amino, -COOR at and -OCOR at ; wherein each R at is independently selected from hydrogen and C 1 -C 4 alkyl.
  • R 1T is C 6 -C 10 aryl substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and amino.
  • R 1T is a group of the following structure: wherein: mt is 0, 1, 2, 3, or 4; R 9T is selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, amino, -COOR at and -OCOR at ; wherein each R at is independently selected from hydrogen and C 1 -C 4 alkyl; and each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, amino, -COOR at and -OCOR at ; wherein each R at is independently selected from hydrogen and C 1 -C 4 alkyl, wherein the wavy line intersects the bond between R 1T and the rest of the molecule.
  • R 1T is a group of the following structure: wherein: R 9T is selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, amino, -COOR at and -OCOR at ; wherein each R at is independently selected from hydrogen and C 1 -C 4 alkyl; and each R 11T is independently selected from hydrogen, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, amino, -COOR at and -OCOR at ; wherein each R at is independently selected from hydrogen and C 1 -C 4 alkyl, wherein the wavy line intersects the bond between R 1T and the rest of the molecule.
  • R 1T is a group of the following structure: wherein the wavy line intersects the bond between R 1T and the rest of the molecule.
  • R 2T is -NR 3T R 4T .
  • a T is selected from CR 5T R 6T , a three- to eight-membered heteroaryl optionally substituted with one or more R 7T , and a three- to eight-membered heterocycloalkyl optionally substituted with one or more R 8T .
  • a 1T is selected from a three- to eight-membered heteroaryl and a three- to eight-membered heterocycloalkyl.
  • a 1T is selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyrrolidinyl, pyrryl, pyrazolidinyl, pyrazolyl, imidazolyl, imidazolidinyl, and diazabicyclo[3.2.1]octanyl.
  • a 1T is selected from piperidinyl, pyrazolyl, and diazabicyclo[3.2.1]octanyl.
  • mt is 0, 1 or 2.
  • R 3T is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.
  • R 3T is selected from hydrogen and C 1 -C 4 alkyl. In some embodiments, R 3T is hydrogen. In some embodiments, R 4T is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. In some embodiments, R 4T is selected from hydrogen and C 1 -C 4 alkyl. In some embodiments, R 4T is hydrogen. In some embodiments, R 5T is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. In some embodiments, R 5T is selected from hydrogen and C 1 -C 4 alkyl. In some embodiments, R 5T is hydrogen.
  • R 3T and R 5T together with the atoms which they are attached to form a five or six membered heterocycloalkyl or a five or six membered heteroaryl.
  • R 6T is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. In some embodiments, R 6T is selected from hydrogen and C 1 -C 4 alkyl. In some embodiments, R 6T is hydrogen.
  • R 7T is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. In some embodiments, R 7T is selected from hydrogen and C 1 -C 4 alkyl. In some embodiments, R 7T is hydrogen.
  • R 8T is selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl. In some embodiments, R8T is selected from hydrogen and C1-C4 alkyl. In some embodiments, R 8T is hydrogen. In some embodiments, R 3T and one R 8T together with the atoms which they are attached to form a five or six membered heterocycloalkyl or a five or six membered heteroaryl. In some embodiments, R 9T is selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, and amino.
  • R 9T is selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and amino. In some embodiments, R 9T is selected from hydroxy and amino. In some embodiments, R 9T is hydroxy. In some embodiments, each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 - C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and amino. In some embodiments, each R 10T is independently selected from halo, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl.
  • each R 10T is independently selected from halo.
  • each R 11T is independently selected from hydrogen, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and amino.
  • each R 11T is independently selected from hydrogen, halo, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl.
  • each R 11T is independently selected from hydrogen, halo, and C 1 -C 4 alkyl.
  • each R 11T is independently selected from hydrogen and halo.
  • the SMARCA binder is of formula 2T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein: mt is 0, 1, 2, 3, or 4;
  • a 1T is selected from a three- to eight-membered heteroaryl optionally substituted with one or more R 7T , and a three- to eight-membered heterocycloalkyl optionally substituted with one or more R 8T ; each R 3T , R 4T , R 7T and R 8T is independently selected from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;
  • R 9T is selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and amino; and each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl, C 1 -C 4
  • mt is 0, 1 or 2;
  • a 1T is selected from a three- to eight-membered heteroaryl and a three- to eight- membered heterocycloalkyl;
  • R 3T and R 4T are both hydrogen;
  • R 9T is hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and amino;
  • each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.
  • mt is 0, 1 or 2;
  • a 1T is selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyrrolidinyl, pyrryl, pyrazolidinyl, pyrazolyl, imidazolyl, imidazolidinyl, and diazabicyclo[3.2.1]octanyl;
  • R 3T and R 4T are both hydrogen;
  • R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and amino;
  • each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.
  • mt is 0, 1 or 2;
  • a 1T is selected from piperidinyl, pyrazolyl, and diazabicyclo[3.2.1]octanyl;
  • R 3T and R 4T are both hydrogen;
  • R 9T is hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and amino;
  • each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halo, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.
  • the SMARCA binder is of formula 3T:
  • the SMARCA2 binder is of formula 4T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker.
  • the SMARCA2 binder is of the formula 5T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein: R 9T is hydroxy or amino; and each R 11T is independently selected from H, and halo.
  • the SMARCA2 binder is of the formula 6T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker. In some embodiments, the SMARCA2 binder is of the formula 7T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein: R 9T is hydroxy or amino; each R 11T is independently selected from H, and halo. In some embodiments, the SMARCA2 binder is of the formula 8T:
  • the SMARCA2 binder is of the formula 9T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein: m is 0, 1, 2, 3, or 4; R 4 is selected from hydrogen and C 1 -C 4 alkyl; R 9 is selected from hydroxy, C 1 -C 4 alkoxy, and amino; and each R 10 is independently selected from hydroxy, C 1 -C 4 alkoxy, halo, C 1 -C 4 alkyl, and amino.
  • mt is 0, 1 or 2; R 4T is hydrogen; R 9T is selected from hydroxy, C 1 -C 4 alkoxy, and amino; and each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, halo and C 1 -C 4 alkyl.
  • the SMARCA2 binder is of the formula 10T:
  • the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein: R 9T is hydroxy or amino; and each R 11T is independently selected from H, and halo.
  • the SMARCA2 binder is of the formula 11T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker.
  • the SMARCA2 binder is of the formula 12T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein: m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; each R 4T , R 7T and R 8T is independently selected from hydrogen and C 1 -C 4 alkyl; R 9T is selected from hydroxy, C 1 -C 4 alkoxy, and amino; and each R 10T is independently selected from hydroxy, C 1 -C 4 alkoxy, halo, C 1 -C 4 alkyl, and amino.
  • the SMARCA2 binder is of the formula 13T: wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein: R 9 is hydroxy or amino; and each R 11 is independently selected from H, and halo.
  • the SMARCA2 binder is of the formula 14T:
  • kinase inhibitors examples include, but are not limited to: 1. Erlotinib Derivative Tyrosine Kinase Inhibitor: where R is a linker attached, for example, via an ether group; 2.
  • the kinase inhibitor sunitinib (derivatized where R is a linker attached, for example, to the pyrrole moiety); 3. Kinase Inhibitor sorafenib (derivatized): (derivatized where R is a linker attached, for example, to the amide moiety); 4.
  • the kinase inhibitor dasatinib (derivatized): (derivatized where R is a linker attached, for example, to the pyrimidine); 5.
  • the kinase inhibitor lapatinib (derivatized): (derivatized where a linker is attached, for example, via the terminal methyl of the sulfonyl methyl group); 6.
  • the kinase inhibitor U09-CX-5279 derivatized where a linker is attached, for example, via the amine (aniline), carboxylic acid or amine alpha to cyclopropyl group, or cyclopropyl group; 7.
  • kinase inhibitors Y1W and Y1X (Derivatized) having the structures: YIX (l-ethyl-3-(2- ⁇ [3-(1-methylethyl)[l,2,4]triazolo[4,3-a]pyridine-6- yl]sulfanyl ⁇ benzyl)urea derivatized where a linker is attached, for example, via the iso-propyl group; Y1W 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2- ⁇ [3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin- 6-yl]sulfanyl ⁇ benzyl)urea derivatized where a linker is attached, for example, preferably via either the iso-propyl group or the tert-butyl group; 8.
  • the kinase inhibitors identified in Schenkel, et al., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors including the compounds 6TP and OTP (Derivatized) having the structures: 6TP 4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide Thienopyridine 19 derivatized where a linker is attached, for example, via the terminal methyl group bound to amide moiety; OTP 4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide Thienopyridine 8 derivatized where a linker is attached, for example, via the terminal methyl group bound to the amide moiety; 9.
  • Biol.176292 including the kinase inhibitors XK9 and NXP (derivatized) having the structures: XK9 N- ⁇ 4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl ⁇ -7-nitro-1 H-indole-2- carboxamide; NXP N- ⁇ 4-[(1E)-N-carbamimidoylethanehydrazonoyl]phenyl ⁇ -1H-indole-3-carboxamide derivatized where a linker is attached, for example, via the terminal hydroxyl group (XK9) or the hydrazone group (NXP); 12.
  • the kinase inhibitor afatinib (derivatized) (N-[4-[(3-chloro-4- fiuorophenyl)amino]-7- [[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)- 2-butenamide) (Derivatized where a linker is attached, for example, via the aliphatic amine group); 13.
  • the kinase inhibitor fostamatinib derivatized ([6-( ⁇ 5-fiuoro-2-[(3,4,5- trimethoxyphenyl)amino]pyrimidin-4-yl ⁇ amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H­ pyrido[3,2-b]- l ,4-oxazin-4-yl]methyl disodium phosphate hexahydrate) (Derivatized where a linker is attached, for example, via a methoxy group); 14.
  • the kinase inhibitor gefitinib (derivatized) (N-(3-chloro-4-fiuoro-phenyl)- 7-methoxy-6- (3-morpholin-4-ylpropoxy)quinazolin-4-amine): (derivatized where a linker is attached, for example, via a methoxy or ether group); 15.
  • the kinase inhibitor lenvatinib (derivatized) (4-[3-chloro-4- (cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide) (derivatized where a linker is attached, for example, via the cyclopropyl group); 16.
  • the kinase inhibitor vandetanib (N-(4-bromo-2- fiuorophenyl)-6- methoxy-7-[(l-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized where a linker is attached, for example, via the methoxy or hydroxyl group); 17.
  • the kinase inhibitor Gleevec also known as Imatinib) (derivatized): (derivatized where R is a linker attached, for example, via the amide group or via the aniline amine group); 18.
  • the kinase inhibitor pazopanib (derivatized) (VEGFR3 inhibitor): (derivatized where R is a linker attached, for example, to the phenyl moiety or via the aniline amine group); 19.
  • the kinase inhibitor AT-9283 (Derivatized) Aurora Kinase Inhibitor (where R is a linker attached, for example, to the phenyl moiety); 20.
  • the kinase inhibitor TAE684 (derivatized) ALK inhibitor (where R is a linker attached, for example, to the phenyl moiety); 21.
  • the kinase inhibitor nilotinib (derivatized) Abl inhibitor (derivatized where R is a linker attached, for example, to the phenyl moiety or the aniline amine group); 22.
  • Kinase Inhibitor NVP-BSK805 (derivatized) JAK2 Inhibitor (derivatized where R is a linker attached, for example, to the phenyl moiety or the diazole group);
  • Kinase Inhibitor crizotinib Derivatized Alk Inhibitor (derivatized where R is a linker attached, for example, to the phenyl moiety or the diazole group); 24.
  • Kinase Inhibitor JNJ FMS (derivatized) Inhibitor (derivatized where R is a linker attached, for example, to the phenyl moiety); 25.
  • the kinase inhibitor foretinib (derivatized) Met Inhibitor (derivatized where R is a linker attached, for example, to the phenyl moiety or a hydroxyl or ether group on the quinoline moiety); 26.
  • the allosteric Protein Tyrosine Phosphatase Inhibitor PTPlB derivatized: derivatized where a linker is attached, for example, at R, as indicated; 27.
  • the inhibitor of SHP-2 Domain of Tyrosine Phosphatase derivatized: derivatized where a linker is attached, for example, at R; 28.
  • the inhibitors (derivatized) of BRAF wt and/or mutant forms):
  • a linker group is attached, for example, at R
  • a linker group e.g. the kinase inhibitor vemurafenib (PLX4032) (derivatized) (propane-1-sulfonic acid ⁇ 3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difiuoro-phenyl ⁇ -amide) (derivatized where a linker is attached, for example, via the sulfonyl propyl group); 29.
  • the kinase inhibitor OSI-930 (derivatized) c-Kit/KDR inhibitor derivatized where a linker is attached, for example, at R; and 32.
  • the kinase inhibitor OSI-906 (derivatized) IGFlR/IR inhibitor derivatized where a linker is attached, for example, at R; (derivatized where "R" designates a site for attachment of a linker on the piperazine moiety).
  • Compounds targeting Human BET Bromodomain-containing proteins include, but are not limited to the compounds associated with the targets as described below, where "R” designates a site for linker attachment, for example: JQl, Filippakopoulos et al. Selective inhibition of BET bromodomains. Nature (2010): 2. I-BET, Nicodeme et al. Supression of Inflammation by a Synthetic Histone Mimic. Nature (2010). Chung et al. Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains. J. Med Chem. (2011): 3.
  • BRD9 Representative examples of BRD9 targeting agents have been developed over the years, including those described in: WO 2014/114721, WO 2016/077375, WO 2016/077378, WO 2016/139361, WO 2019/152440, a paper by Martin L. J.
  • the BRD9 binder may be of formula BRD91a: A 2 wherein: Z 1 is N or CR A ; Z 2 is N or CR B ; Z 3 is N or CR D ; Z 4 is N or CR E ; wherein no more than 3 of Z 1 , Z 2 , Z 3 and Z 4 are N; R A and R E are each independently selected from the group consisting of -H, -O-C 1-3 alkyl and –C 1-3 alkyl; R B and R D are each independently selected from the group consisting of -O-C 1-3 alkyl, -H, -OH, halogen, -NH 2 , -C 1-3 alkyl, -O-C 1-3 haloalkyl, -C 1-3 alkyl-O-C 1-3 alkyl, 4-7 membered heterocycl
  • R C is selected from the group consisting of -H, -Y-R G , -NH 2 , -C 1-3 alkyl and 4-7 membered heterocycloalkyl;
  • Y is absent or is selected from the group consisting of -CR H R I -, -SO 2 - and -CO-;
  • R H and R I are each independently selected from -H or –C 1-3 alkyl; or R H and R I taken together form a –C 3-4 cycloalkyl
  • R G is selected from the group consisting of -NH 2 , -OH, -C 1-3 alkyl, -N(R J R K ), -O-R L , aryl, 5-6 membered heteroaryl, wherein the aryl
  • no more than 1 of Z 1 , Z 2 , Z 3 and Z 4 of formula BRD91a is N.
  • Z 1 is CR A
  • Z 2 is CR B
  • Z 3 is N or CR D
  • Z 4 is CR E
  • the BRD9 binder may be of formula BRD91a’: wherein: R A , R B , R C , R E , Z 3 and A 2 are as defined above and herein.
  • a 2 is selected from formulae BRD91b or BRD91c: wherein the wavy lines intersect the bond between A 2 and the carbon atom positioned ortho to R A and R E , and Z 5 , Z 6 , Z 7 , Z 8 , R M , R S , R T , R U and R V are as defined above and herein.
  • Z 7 is N or CR N
  • Z 5 is N or CR O .
  • R N (with the carbon to which it is bonded) and Z 5 taken together, may combine to form an optionally substituted C 6-10 arene or optionally substituted C 2–9 heteroarene.
  • R N and N may combine to form an optionally substituted N-C 2–4 heteroaryl, as shown below: O wherein the wavy lines intersect the bond between A 2 and the carbon atom positioned ortho to R A and R E , Z 6 and R M are as defined above, and where 1B is an optionally substituted N- C 2–4 heteroarene, such as an optionally substituted 5 membered heteroarene e.g. any one selected from the optionally substituted group consisting of pyrrole, imidazole, pyrazole and triazole (including 1,2,3 and 1,2,4-triazoles).
  • R N and R O taken together with the carbons to which they are bonded may combine to form an optionally substituted C 6-10 arene or optionally substituted C 2–9 heteroarene, as shown below: wherein the wavy lines intersect the bond between A 2 and the carbon atom positioned ortho to R A and R E , Z 6 and R M are as defined above, and where, as stated above, ring 1C is an optionally substituted C 6-10 arene or optionally substituted C 2–9 heteroarene.
  • ring 1C may be an optionally substituted benzene or 5-6 membered heteroarene, such as any one selected from the optionally substituted group consisting of benzene, pyridine, pyrrole, imidazole, pyrimidine, thiophene and pyrazole.
  • R N taken with the carbon atoms to which it is joined
  • Z 5 taken together may form a benzene ring or a 5-6 membered heteroarene ring (e.g.
  • ring 1C may be a benzene ring or a 5-6 membered heteroarene), each of which rings can be optionally and independently substituted with one or more groups selected from halogen, -OH, -NH 2 , -NH- C 1-3 alkyl and –C 1-5 alkyl, C 1-5 haloalkyl, C 1-5 alkoxy, C 1-4 haloalkoxy, 1d, C 3-5 azacycloalkyl, C 2- 5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, wherein the –C 1-5 alkyl group can be optionally substituted with 5-6 membered heteroaryl or phenyl; wherein 1d is: wherein Y 2 is NR R or O; Y 1 is S(O) a or NR R ; each R R is independently H or C1-4alkyl; each R Q is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloal
  • Z 7 is CR N , i.e. A 2 is selected from formula BRD91b’: wherein the wavy line intersects the bond between A 2 and the carbon atom positioned ortho to R A and R E , and Z 5 , Z 6 , R M and R N are as defined above and herein.
  • R M may be selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3- 10 carbocyclyl, C 2-6 alkynyl and H.
  • R M may be selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl and H.
  • R M may be selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 1- 6 haloalkyl and H.
  • R M is selected from the group consisting of –C 1- 5 alkyl, -cyclopropyl, -C 1-4 haloalkyl and H, such as C 1-5 alkyl.
  • R M is C 1- 3 alkyl.
  • R N may be selected from the group consisting of halogen, optionally substituted -C 1-6 alkyl, -H, C(O)C 1-5 alkyl, -NH 2 , optionally substituted amino, –OH, cyano, optionally substituted C 1- 6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 heteroaryl, optionally substituted C 2- 6 alkenyl, optionally substituted C 2-6 heteroalkenyl and thiol.
  • R N may be selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, H, C(O)C 1- 5 alkyl, -NH 2 , -NHC 1-3 alkyl and –OH.
  • R N is selected from the group consisting of halogen, -C 1-5 alkyl, -C 1-3 haloalkyl, -H, C(O)C 1-5 alkyl, -NH 2 , -NHC 1-3 alkyl and –OH.
  • R N may be C 1-5 alkyl or halogen.
  • Z 5 may be N or CR O , where R O is selected from the group consisting of H, halogen, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3- 10 carbocyclyl, optionally substituted C 2–9 heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 heteroaryl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6heteroalkenyl, hydroxy, thiol and optionally substituted amino.
  • R O may be H or optionally substituted C 1-6 alkyl, such as C 1-3 alkyl.
  • R O may be H or – C 1-3 alkyl.
  • R N is -C 1-5 alkyl or halogen, or R N and Z 5 taken together form an optionally substituted 5-6 membered heteroarene or benzene ring.
  • the optionally substituted 5-6 membered heteroarene ring may comprise one or more heteroatoms selected from the group consisting of N, S and O, such as N and S, i.e. the optionally substituted 5-6 membered heteroarene ring may be an N- or S-heteroarene.
  • the optionally substituted 5-6 membered heteroarene ring is any one selected from the optionally substituted group consisting of pyridine, pyrrole, imidazole, pyrimidine, thiophene and pyrazole.
  • the optional substituents may be one or more groups selected from halogen, -OH, -NH 2 , -NH-C 1-3 alkyl and –C 1-5 alkyl, C 1-5 haloalkyl, C 1-5 alkoxy, C 1- 4 haloalkoxy, 1d, C 3-5 azacycloalkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, wherein the –C 1- 5 alkyl group can be optionally substituted with 5-6 membered heteroaryl or phenyl; wherein 1d is: wherein Y 2 is NR R or O; Y 1 is S(O) a or NR R ; each R R is independently H or C 1-4 alkyl; each R Q is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halogen and –C(O)C 1-3 alkyl; a is 0 to
  • the optional substituents may be independently selected from the group consisting of halogen, -OH, -NH 2 , -NH-C 1-3 alkyl –C 1-5 alkyl, C 1-5 haloalkyl, C 1-5 alkoxy and C 1- 4 haloalkoxy.
  • the optional substituents may be independently selected from C 1 -C 4 alkyl, allyl, crotyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 haloalkyl, C 3-5 cycloalkyl, C 1 -C 4 alkoxy, and halo.
  • Z 6 may be N or CR P , where R P is selected from the group consisting of H, halogen, optionally substituted C 1 - 6 alkyl, optionally substituted C 1 - 6 heteroalkyl, optionally substituted C 3 - 1 0 carbocyclyl and optionally substituted C 6 - 10 aryl.
  • R P may be H or optionally substituted C 1-6 alkyl, such as H or C 1-6 alkyl.
  • R P is H or –C 1-3 alkyl, i.e. Z 6 is N, CH or C–C 1-3 alkyl.
  • Z 6 may be CH or C–C 1-3 alkyl.
  • a 2 is selected from formula BRD91b’, wherein formula BRD91b’ is: wherein the wavy line intersects the bond between A 2 and the carbon atom positioned ortho to R A and R E ;
  • R M is selected from the group consisting of –C 1-5 alkyl, -cyclopropyl, -C 1-4 haloalkyl and H;
  • R N is selected from the group consisting of halogen, -C 1-5 alkyl, -C 1-3 haloalkyl, -H, C(O)C 1-5 alkyl, -NH 2 , -NHC 1-3 alkyl and –OH;
  • Z 5 is N or CR O
  • Z 6 is N or CR P wherein only one of Z 5 and Z 6 may be
  • the BRD9 binder may be attached to the linker at any suitable position (provided it has the correct valency and/or is chemically suitable).
  • the linker may be attached to the BRD9 binder by way of a covalent bond between an atom on the linker and an atom forming part of R C , R A , R B , R D or R E .
  • the linker may be attached directly to the ring to which R C , R A , R B , R D and/or R E are bound, i.e. the linker may replace R C , R A , R B , R D or R E .
  • the linker is attached to the BRD9 binder by way of a covalent bond between an atom on the linker and an atom forming part of R C or by way of a covalent bond between an atom on the linker and the atom to which R C would otherwise be bound, i.e. the linker replaces R C .
  • R C and Z 2 or R C and Z 3 taken together e.g.
  • the linker may be attached to the BRD9 binder by way of a covalent bond between an atom on the linker and an atom forming part of the 5-7 membered heterocycloalkyl.
  • the BRD9 binder is of formula BRD91a 1 , BRD91a 2 , BRD91a 3 : wherein the wavy line intersects the bond between the BRD9 binder and the linker; A 2 , Z 1 , Z 2 , Z 3 and Z 4 are as defined above and herein; R C is absent or is as defined above and herein; and ring 1A is a 5-7 membered heterocycloalkane optionally substituted with –C 1-3 alkyl. Ring 1A may comprise one or two heteroatoms independently selected from the list consisting of N, S and O.
  • ring 1A may be selected from the list consisting of pyrrolidine, piperidine, piperazine, morpholine, oxolane, oxane, tetrahydrothiophene and thiane.
  • ring 1A may be an N-heterocycloalkane such as pyrrolidine, piperidine or piperazine.
  • ring 1A is pyrrolidine.
  • the linker is attached to the BRD9 binder by way of a covalent bond between an atom on the linker and an atom forming part of a feature on the BRD9 binder (such as R C ), the linker replaces a chemical group or an atom of the feature with a valency of 1 (such as a hydrogen atom) in order for valencies to be satisfied.
  • a valency of 1 such as a hydrogen atom
  • the linker may replace a methyl group or a hydrogen atom on the feature.
  • the linker may be attached to the BRD9 binder by way of a covalent bond between an atom on the linker and an atom forming part of A 2 , for example an atom forming part of R M , R N , R O , R P , R S , R T , R U , R V , or R W or the linker may replace R M , R N , R O , R P , R S , R T , R U , R V , or R W .
  • the linker may be attached to the BRD9 binder by way of a covalent bond between an atom on the linker and an a tom forming part of the optionally substituted C 6-10arene or optionally substituted C2– 9 heteroarene.
  • the linker may be attached to the BRD9 binder as shown in the structure below: wherein the wavy line intersects the bond between A 2 and the carbon atom positioned ortho to R A and R E ; and R M and Z 6 are as defined above and herein.
  • the linker may be attached to an atom forming part of a substituent bonded to the same positions indicated above.
  • the linker may be attached to an atom forming part of substituent 1d bonded to the same positions indicated above.
  • Z 1 , Z 2 , Z 3 , Z 4 and R C of the BRD9 binder may be defined as follows: Z 1 is N or CR A ; Z 2 is N or CR B ; Z 3 is N or CR D ; Z 4 is N or CR E ; wherein no more than 3 of Z 1 , Z 2 , Z 3 and Z 4 are N; R A and R E are each independently selected from the group consisting of -H, -O-C 1-3 alkyl and –C 1-3 alkyl; R B and R D are each independently selected from the group consisting of -O-C 1-3 alkyl, -
  • R C is selected from the group consisting of -H, -Y-R G , -NH 2 , -C 1-3 alkyl and 4-7 membered heterocycloalkyl;
  • Y is absent or is selected from the group consisting of -CR H R I -, -SO 2 - and -CO-;
  • R H and R I are each independently selected from -H or –C 1-3 alkyl; or R H and R I taken together form a –C 3-4 cycloalkyl
  • R G is selected from the group consisting of -NH 2 , -OH, -C 1-3 alkyl, -N(R J R K ), -O-R L , aryl, 5-6 membered heteroaryl, wherein the aryl
  • R A , R B , R D and R E are independently selected from the group consisting of -O-C 1- 3 alkyl, -H, halogen, -O-C 1-3 haloalkyl, -OH, -NH 2 , -C 1-3 alkyl, -C 1-3 alkyl-NH 2 , -C 1- 3 alkyl-N(-C 1-3 alkyl) 2 and -N(C 1-3 alkyl) 2 ; or (ii) R A , R D and R E are independently selected from the group consisting of -O-C 1-3 alkyl, -H, halogen, -O-C 1-3 haloalkyl, -OH, -NH 2 , -C 1-3 alkyl, -C 1-3 alkyl-NH 2 , -C 1-3 alkyl-N(-C 1- 3 alkyl
  • the 5-7 membered heterocycloalkyl may be as defined above for ring 1A.
  • R A , R B , R D and R E are independently selected from the group consisting of -O-C 1-3 alkyl, -H, halogen, -O-C 1-3 haloalkyl, -OH, -NH 2 , -C 1-3 alkyl, -C 1-3 alkyl-NH 2 , -C 1-3 alkyl-N(-C 1-3 alkyl) 2 and -N(C 1-3 alkyl) 2 .
  • R A , R B , R D and R E may be independently selected from the group consisting of -O-C 1-3 alkyl, -H, halogen and -O-C 1- 3 haloalkyl.
  • at least one of R A , R B , R D and R E may be –H.
  • at least one of R A and R B may be –H.
  • at least two of R A , R B , R D and R E are –H.
  • at least one of R A , R B , R D and R E is selected from the group consisting of -O-C 1-3 alkyl, halogen and -O-C 1-3 haloalkyl.
  • R B and R E are selected from the group consisting of -O-C1-3alkyl, halogen and -O-C1-3haloalkyl.
  • R C is –H or -Y-R G .
  • Y may be -CR H R I - or -CO-, wherein R H and R I are as defined above.
  • Each of R H and R I may be -H; or R H and R I taken together may form a –C 3- 4 cycloalkyl.
  • R G may be as defined above, or may be selected from the group consisting of -NH 2 , -OH, -C 1- 3 alkyl -N(R J R K ), -O-R L and optionally substituted 4- to 7- membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, where R J , R K and R L and the optional substituents of the 4- to 7- membered monocyclic heterocycloalkyl and 7- to 12-membered bicyclic heterocycloalkyl are as defined above.
  • R J may be -H or –C 1-3 alkyl and R K may be selected from –C 1-3 alkyl, optionally substituted 4- to 7- membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl.
  • R L may be –C 1-3 alkyl.
  • R G or R K is an optionally substituted 4- to 7-membered monocyclic heterocycloalkyl
  • the optionally substituted 4- to 7- membered monocyclic heterocycloalkyl may be a 5- to 7- membered monocyclic heterocycloalkyl comprising between one and three ring heteroatoms selected from N, O and S.
  • the optionally substituted 4- to 7- membered monocyclic heterocycloalkyl may be a 5- to 7- membered monocyclic heterocycloalkyl comprising one or two ring heteroatoms selected from N.
  • the optionally substituted 4- to 7- membered monocyclic heterocycloalkyl may be piperazinyl, piperidinyl or diazepanyl (each of which may optionally comprise between one and three substituents as described herein).
  • R G or R K is an optionally substituted 7- to 12-membered bicyclic heterocycloalkyl
  • the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be a bridged bicyclic ring or a spirocyclic bicyclic ring (i.e it may comprise two rings joined at a spiro centre).
  • the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be a bridged piperazinyl or bridged piperidinyl.
  • the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be an optionally substituted spirocyclic bicyclic heterocycloalkyl comprising between one and three ring heteroatoms selected from N, O and S (e.g. between one and two ring heteroatoms selected from N).
  • the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be spirocyclic and comprise a first 5- or 6-membered ring and a second 3- to 6-membered ring.
  • RC may be any one selected from: wherein Y is CR H R I (e.g.
  • R G1 and R G2 are each independently selected from H and C 1 -C 3 alkyl; R J is as defined above and herein; and L shows the point of attachment of the linker.
  • both the Y and L groups may be attached to the heterocyclic ring(s) by way of a covalent bond between an atom on the Y and L group respectively and an atom on the heterocyclic ring. These groups may be bonded at any chemically suitable position provided valencies are satisfied (e.g. by replacing each replacing a H atom).
  • R C may be any one selected from: wherein Y is CR H R I (e.g. CH 2 ); and L shows the point of attachment of the linker.
  • R C is any one selected from the group consisting of , –CH 2 N(C 1-3 alkyl) 2 , -C(O)N(C 1-3 alkyl) 2 , -C(CH 2 CH 2 )N(C 1-3 alkyl) 2 , and CH 2 OCH 3 , wherein the wavy lines intersect the bond between R C and the rest of the BRD9 binder and the bond between R C and the linker.
  • the BRD9 binder is of formula BRD91e, BRD91f or BRD91g: wherein the wavy line intersects the bond between the BRD9 binder and the linker; R A , R B , R E , R M , R N , Z 3 , Z 5 and Z 6 are as defined above; R C is absent, or is as defined for R C above and herein; ring 1A is a 5-7 membered heterocycloalkane optionally substituted with –C 1-3 alkyl; and ring 1D is an optionally substituted C 6-10 arene or optionally substituted C 2–9 heteroarene.
  • ring 1D is optionally substituted benzene or an optionally substituted 5-6 membered heteroarene.
  • the 5-6 membered heteroarene may comprise one or more heteroatoms selected from the group consisting of S, N and O, such as S.
  • ring 1D may be a 5-6 membered N-heteroarene or S-heteroarene, for example any one selected from the group consisting of thiophene, pyrazole, imidazole, pyrrole, pyrimidine and pyridine.
  • ring 1D is thiophene fused to the rest of the BRD9 binder at the 2’ and 3’ positions and, in even more particular examples, bonded to the linker by way of a covalent bond between an atom on the linker and the carbon atom at the 5’ position of the thiophene.
  • the BRD9 binder may be of formula BRD91g’: wherein the wavy line intersects the bond between the BRD9 binder and the linker; and wherein R A , R B , R C , R E , R M , Z 3 , and Z 6 are as defined above.
  • ring 1A is pyrrolidine.
  • ring 1A is pyrrolidine fused to the rest of the BRD9 binder at the 3’ and 4’ positions and, in even more particular embodiments, bonded to the linker by way of a covalent bond between an atom on the linker and the nitrogen atom of the pyrrolidine.
  • the BRD9 binder may be of formula BRD91f’: wherein the wavy line intersects the bond between the BRD9 binder and the linker; and wherein R A , R E , R M , R N , Z 3 , Z 5 and Z 6 are as defined above and herein.
  • the BRD9 binder is of formula BRD91e, BRD91f’ or BRD91g’.
  • the BRD9 binder is any one of formulae BRD91ea to BRD91eh, BRD91fa to BRD91fh and BRD91ga: wherein the wavy line intersects the bond between the BRD9 binder and the linker;
  • R A , R B , R E , R M , Z 3 and Z 6 are as defined above and herein;
  • R C is absent, or is as defined above and herein;
  • R N is as defined above and herein, for example is selected from the group consisting of halogen, -C 1-5 alkyl, -C 1-3 haloalkyl, -H, C(O)C 1-5 alkyl, -NH 2 , -NHC 1-3 alkyl and –OH;
  • R O is as defined above and herein, for example is -H or –C 1-3 alkyl;
  • each R X is as defined for the optional substituents of the optionally substituted C 6-10 aryl or optionally substituted
  • the BRD9 binder is according to formula BRD91ea’: wherein the wavy line intersects the bond between the BRD9 binder and the linker; R A and R E are as defined above and herein, for example are each independently selected from H and -O-C 1-3 alkyl; R B and R D are as defined above and herein, for example are each independently selected from -O-C 1-3 alkyl, -H, - halo, -C 1-3 alkyl, and -O-C 1-3 haloalkyl; R C is absent, or is –Y-R G ; Y is selected from the group consisting of -CR H R I -, and -CO-; R H and R I are each independently selected from -H or –C 1-3 alkyl; or R H and R I taken together form a –C 3-4 cycloalkyl; R G is selected from the group consisting of
  • the BRD9 binder is any one of formulae BRD91h to BRD91z and BRD92a to B
  • R C is absent, or is –Y-R G ;
  • Y is selected from the group consisting of -CR H R I -, and -CO-;
  • R H and R I are each -H; or R H and R I taken together form a –C 3-4 cycloalkyl;
  • R G is selected from the group consisting of –N(R J R K ) (e.g.
  • R G is -N(C 1-3 alkyl)-, -O- or
  • R C may be any one selected from:
  • HSP90 inhibitors useful according to the present disclosure include but are not limited to: 1.
  • the HSP90 inhibitor p54 (modified) (8-[(2,4-dimethylphenyl)sulfanyl]- 3]pent-4-yn-l-yl-3H- purin-6-amine): where a linker is attached, for example, via the terminal acetylene group; 3.
  • HSP90 inhibitor PU3 having the structure: where a linker group is attached, for example, via the butyl group; and 5.
  • the HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,l0E,12S,13R,14S,16R)- 13-hydroxy- 8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[l6.3.
  • HDM2/MDM2 inhibitors of the invention include, but are not limited to: 1.
  • HDAC Inhibitors useful in some examples of the disclosure include, but are not limited to: 1. Finnin, M. S. et al. Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. (1999, Nature, 40:188-193). (Derivatized where "R" designates a site for attachment, for example, of a linker; and 2.
  • Human Lysine Methyltransferase inhibitors useful in some examples of the disclosure include, but are not limited to: 1. Chang et al. Structural Basis for G9a-Like protein Lysine Methyltransferase Inhibition by BIX-1294 (2009, Nat. Struct. Biol.,16(3):312).
  • Angiogenesis inhibitors useful in some aspects of the disclosure include, but are not limited to: 1.
  • GA-1 (derivatized) and derivatives and analogs thereof, having the structure(s) and binding to linkers as described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, (2003 Dec.,Mol. Cell Proteomics,2(12):1350- 1358); 2.
  • Estradiol (derivatized), which may be bound to a linker as is generally described in Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, (2008, Oncogene 27:7201-7211); 3.
  • Estradiol, testosterone (derivatized) and related derivatives including but not limited to DHT and derivatives and analogs thereof, having the structure(s) and binding to a linker as generally described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, (2003 Dec., Mol. Cell Proteomics, 2(12):1350- 1358); and 4.
  • Immunosuppressive compounds useful in some examples of the disclosure include, but are not limited to: 1.
  • AP21998 (derivatized), having the structure(s) and binding to a linker as is generally described in Schneekloth, et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation (2004, J. Am. Chem. Soc., 126:3748-3754); 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (Derivatized where a linker is bound, e.g. to any of the hydroxyls) and beclometasone dipropionate (Derivatized where a linker is bound, e.g. to a proprionate); 3.
  • Glucocorticoids e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone
  • beclometasone dipropionate Derivatized where a linker is bound,
  • Methotrexate (Derivatized where a linker can be bound, e.g. to either of the terminal hydroxyls); 4. Ciclosporin (Derivatized where a linker can be bound, e.g. at a of the butyl groups); 5. Tacrolimus (FK-506) and rapamycin (Derivatized where a linker group can be bound, e.g. at one of the methoxy groups); and 6. Actinomycins (Derivatized where a linker can be bound, e.g. at one of the isopropyl groups). IX.
  • Compounds targeting the aryl hydrocarbon receptor (AHR) include, but are not limited to: 1. Apigenin (Derivatized in a way which binds to a linker as is generally illustrated in Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007); and 2.
  • SRl and LGC006 (derivatized such that a linker is bound), as described in Boitano, et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells (2010 Sep., Science, 329(5997):1345-1348).
  • XI Compounds Targeting FKBP: (Derivatized where "R” designates a site for linker attachment).
  • TR Compounds Targeting Thyroid Hormone Receptor (TR) 1. Thyroid Hormone Receptor Ligand (derivatized) (Derivatized where "R” designates a site for linker attachment and MOMO indicates a methoxymethoxy group).
  • TR Thyroid Hormone Receptor Ligand
  • Inhibitor of HIV integrase Isentress (derivatized) (Derivatized where "R” designates a site for linker attachment). See, 2010, J. Med. Chem., 53:6466.
  • XVII Compounds targeting HCV Protease 1. Inhibitors of HCV Protease (derivatized) (Derivatized where "R” designates a site for linker attachment).
  • XVIII Compounds targeting Acyl­protein Thioesterase­1 and ­2 (APTl and APT2) 1. Inhibitor of APTl and APT2 (derivatized) (Derivatized where "R” designates a site for linker attachment). See 2011, Angew. Chem. Int.
  • the compound targeting Usp1 is a compound of formula USP1, USP2, or USP3: wherein: A is an aryl or heteroaryl, each of which is optionally substituted with any one or more selected from the group consisting of C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, halo, hydroxyl and amino; B is a heteroaryl comprising at least one N ring atom, optionally substituted with any one or more selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, halo, hydroxyl and amino; R 1 and R 1’ are each independently selected from H and C 1-2 alkyl; n is 1 to 3; R
  • A, B, R 3 , X 1 , X 2 , R 6 , L and Z are as defined above for formula USP1A, USP2A, USP3A, USP1, USP2, and USP3.
  • Representative examples of groups A, B, Y, X 1 , X 2 , X 3 , X 4 , R 1 , R 1’ , R 2 , R 3 , R 4 , R 5 and R 6 are now provided below which are applicable to any one or more of the formulae described herein in relation to compounds targeting Usp1 (unless otherwise indicated) (formulae USP1A, USP2A, USP3A, USP1, USP2, USP3, USP1a, USP2a, and USP3a).
  • A may be an aryl or heteroaryl, each of which is optionally substituted with any one or more selected from the group consisting of C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 1- 4 haloalkyl, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, halo, hydroxyl and amino.
  • A is a heteroaryl, it is optionally substituted at one or more carbon or heteroatoms.
  • A may be contain one or more nitrogen atoms, such as two nitrogen atoms.
  • the heteroaryl is monocyclic.
  • the heteroaryl is a N-heteroaryl.
  • A is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, optionally substituted with any one or more substituents selected from the group consisting of C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, halo, hydroxyl and amino.
  • A may be selected from the group consisting of phenyl, pyrimidinyl and pyrazolyl, optionally substituted with any one or more substituents selected from the group consisting of C 1-4 alkyl (e.g. isopropyl or methyl), C 3-7 cycloalkyl (e.g. cyclopropyl), C 1-4 alkoxy (e.g. methoxy), C 1-4 haloalkyl (e.g. C 1-4 fluoroalkyl, such as trifluoromethyl), C 3-7 cyclohaloalkyl (e.g. C 3-7 cyclofluoroalkyl), C 1-4 haloalkoxy (e.g.
  • C 1-4 fluoroalkoxy such as difluoromethoxy
  • halo e.g. chloro or fluoro, such as chloro
  • A may be selected from the group consisting of phenyl, pyrimidinyl and pyrazolyl, optionally substituted with any one or two substituents selected from the group consisting of C 1-4 alkyl (e.g. isopropyl or methyl), C 3-7 cycloalkyl (e.g. cyclopropyl), C 1-4 alkoxy (e.g. methoxy), C 1-4 haloalkoxy (e.g. difluoromethoxy) and halo (e.g. chloro).
  • C 1-4 alkyl e.g. isopropyl or methyl
  • C 3-7 cycloalkyl e.g. cyclopropyl
  • C 1-4 alkoxy e.g. methoxy
  • C 1-4 haloalkoxy e.g. difluo
  • A is selected from the group consisting of phenyl and pyrimidinyl, optionally substituted with any one or two substituents selected from the group consisting of C 1-4 alkyl (e.g. isopropyl), C 3-7 cycloalkyl (e.g. cyclopropyl), and C 1- 4 alkoxy (e.g. methoxy).
  • A may be selected from N-alkyl 4-alkyl pyrazolyl, 4,6-dialkyl pyrimidinyl and, 2,4-dialkyl pyridinyl (where each of the alkyl groups are C 1-4 alkyl).
  • suitable A groups include, but are not limited to: wherein R C is selected from the group consisting of methoxy, cyclopropyl, and difluoromethoxy. where R A is methyl, ethyl, fluoro or difluorotrifluoroethyl.
  • the line intersected by a wavy line represents the covalent bond between the exemplary A groups shown above and a carbon atom on the heteroaryl core attached to the A group (as illustrated by the various formulae described herein).
  • B is a heteroaryl comprising at least one N ring atom, optionally substituted with any one or more selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, halo, hydroxyl and amino.
  • B is optionally substituted at one or more carbon or heteroatoms.
  • B is a monocyclic five- or six-membered heteroaryl comprising at least one N ring atom (e.g. comprising 1, 2 or 3 N ring atoms).
  • B may be selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, optionally substituted with any one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, halo, hydroxyl and amino.
  • B is a monocyclic five- membered heteroaryl. Sometimes, B comprises at least 2 nitrogen atoms.
  • B may be selected from the group consisting of imidazolyl, pyrazolyl and triazolyl (e.g.1, 2, 3-triazolyl), optionally substituted with any one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, and halo.
  • B may be selected from the group consisting of imidazolyl, pyrazolyl and triazolyl (e.g.1, 2, 3-triazolyl), optionally substituted with any one or more substituents selected from the group consisting of C 1-4 alkyl (e.g. isopropyl, methyl or ethyl), C 1-4 haloalkyl (e.g. trifluoromethyl or fluoroethyl), and C 1-4 alkoxy (such as methoxy).
  • C 1-4 alkyl e.g. isopropyl, methyl or ethyl
  • C 1-4 haloalkyl e.g. trifluoromethyl or fluoroethyl
  • C 1-4 alkoxy such as methoxy
  • suitable B groups include, but are not limited to: where Q A is selected from methyl, isopropyl, ethyl, fluoroethyl and methoxy; where Q E is selected from isopropyl, methyl, ethyl, and fluoroethyl.
  • the line intersected by a wavy line represents the covalent bond between the exemplary B groups shown above and a carbon atom on the aryl core attached to the B group (as illustrated by the various formulae described herein).
  • Y may be an aryl or heteroaryl, each of which is optionally substituted with any one or more selected from the group consisting of C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, C 1- 4 haloalkyl, C 3-7 cyclohaloalkyl, C 1-4 haloalkoxy, halo, hydroxyl and amino.
  • Y is a bi-radical linking B with CR 1 R 1’ .
  • References to any monoradical species in relation to Y are intended to mean bi-radical species able to link B with CR 1 R 1’ .
  • phenyl means a biradical benzene group linking B with CR 1 R 1’ .
  • B and CR 1 R 1 ’ are positioned para to one another.
  • Y is a heteroaryl, it is a monocyclic 6-membered heteroaryl.
  • the heteroaryl is typically a N-heteroaryl comprising at least one nitrogen atom. Often, the N-heteroaryl comprises two nitrogen atoms.
  • Y may be phenyl, pyrimidinyl (such as pyrimidin-1,5-diyl), or pyridinyl, optionally substituted with any one or more substituents selected from the group consisting of halo and C 1-4 alkoxy.
  • Representative examples of Y include, but are not limited to: where Z A is selected from H and halo (e.g. F); and Z C is selected from H and methoxy; and As stated above, R 1 and R 1’ are each independently selected from H and C 1-2 alkyl (e.g. methyl). By way of example, R 1 and R 1’ may each be H.
  • n may be 1 to 3. In some examples, n is 1.
  • R 2 and R 4 are each independently selected from the group consisting of H and C 1 - 4 alkyl (e.g. methyl). By way of example, R 2 and R 4 may both be H.
  • the bifunctional molecule may comprise a compound of formula USP1a, USP2a or USP3a: wherein A, B, R 3 , X 1 , X 2 and X 4 are as defined above (and herein) for formula USP1, USP2 and USP3.
  • X 1 and X 2 are each independently selected from the group consisting of N, C-L-Z and C-R 5 , where R 5 is selected from the group consisting of H and C 1 -C 4 alkyl; and wherein one of X 1 and X 2 is C-L- Z.
  • X 1 is C-L-Z
  • X 2 may be N or C-R 5 , wherein R 5 is selected from the group consisting of H and C 1 -C 4 alkyl (e.g. methyl).
  • X 1 is C-L-Z
  • X 2 may be CH.
  • X 1 may be N or C-R 5 , wherein R 5 is selected from the group consisting of H and C 1 -C 4 alkyl (e.g. methyl).
  • R 5 is selected from the group consisting of H and C 1 -C 4 alkyl (e.g. methyl).
  • X 2 may be CH.
  • the bifunctional molecules comprise a compound of formula USP2b, USP2c, USP2d or USP2e: wherein A, B, L and Z are as defined above and herein in respect of the Usp target binding ligand.
  • X 3 and X 4 are independently selected from the group consisting of CR 6 L-Z and CR 6 2, where each R 6 is independently selected from the group consisting of H and C1-4 alkyl; and wherein one of X 3 and X 4 is CR 6 L-Z.
  • X 3 is CR 6 L-Z
  • X 4 may be CR 6 2, wherein each R 6 is independently selected from the group consisting of H and C 1 - 4 alkyl (e.g. methyl).
  • X 3 may be CH-L-Z and X 4 may be CH 2 .
  • X 3 may be CR 6 2, wherein each R 6 is independently selected from the group consisting of H and C 1 - 4 alkyl (e.g. methyl).
  • R 6 is independently selected from the group consisting of H and C 1 - 4 alkyl (e.g. methyl).
  • X 4 may be CH-L-Z and X 3 may be CH 2 .
  • compound targeting Usp1 is a compound of formula USP3b, USP3c, USP3d or USP3e:
  • L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • XXI Compounds targeting apoptotic & anti­apoptotic factors (including Bcl2 and Bcl­ XL) where L shows the position of attachment of the linker.
  • the present disclosure also encompasses joining or coupling to the linker at any other chemically suitable position on this target protein binding ligand.
  • the disclosure also includes various deuterated forms of the compounds disclosed herein, or of any of the Formulae disclosed herein, including Formulae (ZI), (ZII), (ZIIIa to ZIIIf), (ZIVa to ZIVj), (I), (II) (III), (IV), (IVa), (ZV), (V), (VI) and (VIa); (EGFR1), (EGFR2) and (EGFR3); (KRAS1), (KRAS2), and (KRAS3); (C1) to (C12); (BRD91), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, 10T, 11T, 12T, 13T, 14T or (USP1A), (USP2A), and (USP3A) (inc.
  • Formulae ZI), (ZII), (ZIIIa to ZIIIf), (ZIVa to ZIVj), (I), (II) (III), (IV), (IVa), (ZV), (V
  • Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom.
  • deuterated materials such as alkyl groups may be prepared by conventional techniques (see for example: methyl-d 3 -amine available from Aldrich Chemical Co., Milwaukee, WI, Cat. No.489,689-2).
  • the disclosure also includes isotopically-labelled compounds which are identical to those recited in any of the Formulae disclosed herein, including Formulae (ZI), (ZII), (ZIIIa to ZIIIf), (ZIVa to ZIVj), (I), (II) (III), (IV), (IVa), (ZV), (V), (VI) and (VIa); (EGFR1), (EGFR2) and (EGFR3); (KRAS1), (KRAS2), and (KRAS3); (C1) to (C12); (BRD91), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, 10T, 11T, 12T, 13T, 14T or (USP1A), (USP2A), and (USP3A) (inc.
  • Formulae ZI), (ZII), (ZIIIa to ZIIIf), (ZIVa to ZIVj), (I), (II) (III), (IV), (IVa), (ZV),
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3 H, 11 C, 14 C, 18 F, 123 I or 125 I.
  • Isotopically labelled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H or 14 C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).
  • Degradation activity Degradation may be determined by measuring the amount of a target protein in the presence of a bifunctional molecule as described herein and/or comparing this to the amount of the target protein observed in the absence of the bifunctional molecule. For example, the amount of target protein in a cell that has been contacted and/or treated with a bifunctional molecule as described herein may be determined. This amount may be compared to the amount of target protein in a cell that has not been contacted and/or treated with the bifunctional molecule (e.g. as a control). If the amount of target protein is decreased in the cell contacted and/or treated with the bifunctional molecule, the bifunctional molecule may be considered as facilitating and/or promoting the degradation and/or proteolysis of the target protein.
  • the amount of the target protein can be determined using methods known in the art, for example, by performing immunoblotting assays, Western blot analysis and/or ELISA with cells that have been contacted and/or treated with a bifunctional molecule.
  • Selective degradation and/or increased proteolysis may be considered to have occurred if at least a 10% decrease in the amount of a target protein is observed compared to the control, for example, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% following administration of the bifunctional molecule to the cell.
  • selective degradation and/or increased proteolysis may be considered to have occurred if at least a 10% decrease in the amount of a target protein is observed, (e.g.
  • the bifunctional molecule may be administered at any concentration, e.g. a concentration between 0.01 nM to 10 ⁇ M , such as 0.01nM, 0.1nM, 1 nM, 10nM, 100 nM, 1 ⁇ M, and 10 ⁇ M.
  • an increase of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or approximately 100% in the degradation of the target protein is observed following administration of the bifunctional molecule at a concentration of approximately 100 nM (e.g. following an incubation period of approximately 8 hours).
  • One measure of degrader activity of the bifunctional molecules is the DC 50 value.
  • DC 50 is the concentration required to reach 50% of the maximal degradation of the target protein.
  • the bifunctional molecules described herein may comprise a DC 50 of less than or equal to 10000 nM, less than or equal to 1000 nM, less than or equal to 500 nM, less than or equal to 100 nM or less than or equal to 75 nM.
  • the bifunctional molecules comprise a DC 50 less than or equal to 50 nM, less than or equal to 25 nM, or less than or equal to 10 nM.
  • Another measure of the degrader activity of the bifunctional molecules is the D max value.
  • D max represents the maximal percentage of target protein degradation.
  • the bifunctional molecules described herein may comprise a D max of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or about 100%.
  • Yet another measure of the efficacy of the described bifunctional molecules may be their effect on cell viability and/or their IC 50 value.
  • an anti-proliferative effect of a bifunctional molecule as described herein may be assessed in a cell viability assay to provide an IC 50 value.
  • the IC 50 value represents the concentration at which 50% cell viability was observed in the cell viability assay (following administration of a bifunctional molecule as described herein).
  • the bifunctional molecules described herein may comprise an IC50 of less than 1000nM, less than 500nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 20 nM, or less than 10 nM. In some cases, the bifunctional molecules described herein may comprise an IC50 value of less than 5 nM.
  • compositions comprising the bifunctional molecules described herein.
  • the bifunctional molecule may be suitably formulated such that it can be introduced into the environment of the cell by a means that allows for a sufficient portion of the molecule to enter the cell to induce degradation of the target protein.
  • a pharmaceutical composition comprising a bifunctional molecule as described herein together with a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, phosphate buffer solutions and/or saline. Pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • compositions described above may alternatively or additionally include, an appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • Pharmaceutical compositions may be present in any formulation typical for the administration of a pharmaceutical compound to a subject.
  • compositions include, but are not limited to, capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal and rectal administration.
  • compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), topical (including dermal, buccal and sublingual), rectal, nasal and pulmonary administration e.g., by inhalation.
  • the composition may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Methods typically include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Pharmaceutical compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free- flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent.
  • Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope.
  • the bifunctional molecules may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food.
  • the granules may be packaged, e.g., in a sachet.
  • Compositions suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.
  • compositions for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release-controlling matrix, or is coated with a suitable release-controlling film.
  • Pharmaceutical compositions suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles. Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers, which are sealed after introduction of the formulation until required for use.
  • the bifunctional molecule may be in powder form, which is constituted with a suitable vehicle, such as sterile, pyrogen- free water, before use.
  • the pharmaceutical composition may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins.
  • Pharmaceutical compositions suitable for topical formulation may be provided for example as gels, creams or ointments.
  • the bifunctional molecules described herein may be present in the pharmaceutical compositions as a pharmaceutically and/or physiologically acceptable salt, solvate or derivative.
  • pharmaceutically acceptable salt refers to those salts, which are generally considered suitable for use in medicine (including in a veterinary context).
  • pharmaceutically acceptable salts may be those which can be contacted with the tissues of a mammalian subject (e.g. humans) without undue toxicity, irritation, allergic response or the like.
  • suitable pharmaceutically acceptable salts S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, the entire contents of which are incorporated herein by reference.
  • Representative examples of pharmaceutically and/or physiologically acceptable salts of the bifunctional molecules of the disclosure may include, but are not limited to, acid addition salts formed with organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, malonic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, malonic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids
  • salts include (but are not limited to) adipate, alginate, ascorbate, aspartate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, pivalate, propionate, stearate
  • salts that may be derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 – 4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts may include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • Pharmaceutically and/or physiologically functional derivatives of compounds of the present invention are derivatives, which may be converted in the body into the parent compound. Such pharmaceutically and/or physiologically functional derivatives may also be referred to as "pro- drugs" or “bioprecursors". Pharmaceutically and/or physiologically functional derivatives of compounds of the present disclosure may include hydrolysable esters or amides, particularly esters, in vivo. It may be convenient or desirable to prepare, purify, and/or handle a corresponding pharmaceutically and/or physiologically acceptable solvate of the bifunctional molecules described herein, which may be used in the any one of the uses/methods described. The term solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent.
  • the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.
  • the moiety Z may form part of a bifunctional molecule intended for use in a method of targeted protein degradation, wherein the moiety Z acts to modulate, facilitate and/or promote proteasomal degradation of the target protein.
  • a use of the moiety Z or a compound comprising moiety Z as described herein (e.g. as defined in any one of formula (I) to (V)) in a method of targeted protein degradation e.g.
  • moiety Z may find particular application as a promoter or facilitator of targeted protein degradation.
  • moiety Z or a compound comprising moiety Z e.g. as defined in any one of formula (I) to (V)
  • the bifunctional molecules of the present disclosure may modulate, facilitate and/or promote proteasomal degradation of a target protein.
  • a method of selectively degrading and/or increasing proteolysis of a target protein in a cell comprising contacting and/or treating the cell with a bifunctional molecule as described herein.
  • the method may be carried out in vivo or in vitro.
  • a method of selectively degrading and/or increasing proteolysis of a target protein in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a bifunctional molecule of the present disclosure.
  • the bifunctional molecules of the present disclosure may find application in medicine and/or therapy.
  • the bifunctional molecules of the present disclosure may find use in the treatment and/or prevention of any disease or condition, which is modulated through the target protein.
  • the bifunctional molecules of the present disclosure may be useful in the treatment of any disease, which is modulated through the target protein by lowering the level of that protein in the cell, e.g. cell of a subject.
  • Diseases and/or conditions that may be treated and/or prevented by the molecules of the disclosure include any disease, which is associated with and/or is caused by an abnormal level of protein activity.
  • diseases and conditions include those whose pathology is related at least in part to an abnormal (e.g. elevated) level of a protein and/or the overexpression of a protein.
  • the bifunctional molecules may find use in the treatment and/or prevention of diseases where an elevated level of a protein is observed in a subject suffering from the disease.
  • the diseases and/or conditions may be those whose pathology is related at least in part to inappropriate protein expression (e.g., expression at the wrong time and/or in the wrong cell), excessive protein expression or expression of a mutant protein.
  • a mutant protein disease is caused when a mutant protein interferes with the normal biological activity of a cell, tissue, or organ. Accordingly, there is provided a method of treating and/or preventing a disease or condition, which is associated with and/or is caused by an abnormal level of protein activity, which comprises administering a therapeutically effective amount of a bifunctional compound as described herein.
  • diseases and/or conditions that may be treated and/or prevented by the use of the described bifunctional compounds include (but are not limited to) cancer, asthma, multiple sclerosis, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot- Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease, (PKDl) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease, and Turner syndrome.
  • cancer but are not limited to) cancer, asthma, multiple sclerosis, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder
  • Alzheimer's disease Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barre syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive- compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, and Vasculitis.
  • Alzheimer's disease Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervos
  • Yet further examples include aceruloplasminemia, Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, Anemia, Angiokeratoma Corporis Diffusum, Angiomatosis retinae (
  • cancers that may be treated and/or prevented using the described bifunctional molecules include but, are not limited to squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,
  • T-lineage Acute lymphoblastic Leukemia T-ALL
  • T-lineage lymphoblastic Lymphoma T-LL
  • Peripheral T-cell lymphoma Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
  • the term “patient” or “subject” is used to describe an animal, such as a mammal (e.g. a human or a domesticated animal), to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided.
  • the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc.
  • a domesticated animal such as a dog or cat
  • a farm animal such as a horse, cow, sheep, etc.
  • the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.
  • Assays The disclosure also encompasses a method of screening bifunctional molecules to identify suitable target protein binding ligands and linkers for use in the bifunctional molecules described herein, e.g. a bifunctional molecule that is able to effectively modulate, facilitate and/or promote proteolysis of a target protein.
  • This method may assist in identifying suitable linkers for a particular target protein binding partner such that the level of degradation is further optimised.
  • the method may comprise: a. providing a bifunctional molecule comprising: (i) a first ligand comprising a structure according to Z (as defined in any of the formulae for Z disclosed herein); (ii) a second ligand that binds to a target protein (a target protein binding ligand); and (iii) a linker that covalently attaches the first and second ligands; b. contacting a cell with the bifunctional molecule; and c. detecting degradation of the target protein in the cell.
  • This method may further comprise the steps of: d.
  • a step of detecting degradation of the target protein may comprise detecting changes in levels of a target protein in a cell. For example, a reduction in the level of the target protein indicates degradation of the target protein.
  • the method may further comprise providing a plurality of linkers, each one being used to covalently attach the first and second ligands together to form a plurality of bifunctional molecules.
  • the level of degradation provided by each one of the plurality of bifunctional molecules may be detected and compared. Those bifunctional molecules showing higher levels of target protein degradation indicate preferred and/or optimal linkers for use with the selected target protein binding partner.
  • the method may be carried out in vivo or in vitro.
  • the disclosure also provides a library of bifunctional molecules, the library comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of Z moieties covalently linked to a selected target protein binding partner.
  • the target protein binding partner may be pre-selected and the Z moiety may not be determined in advance.
  • the library may be used to determine the activity of a candidate Z moiety of a bifunctional molecule in modulating, promoting and/or facilitating selective protein degradation of a target protein.
  • the disclosure also includes a library of bifunctional molecules, the library comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of target protein binding ligands and a selected Z moiety.
  • the Z moiety of the bifunctional molecule may be pre-selected and the target protein may not be determined in advance.
  • the library may be used to determine the activity of a putative target protein binding ligand and its value as a binder of a target protein to facilitate target protein degradation.
  • Methods of manufacture According to a further aspect of the disclosure, there is provided a method of making a bifunctional molecule as described herein.
  • the method of making the bifunctional molecule may comprise the steps of: (a) providing a first ligand or moiety comprising a structure according to Z (as defined in any one of the formulae for Z disclosed herein); (b) providing a second ligand or moiety that binds to a target protein (e.g.
  • the method of making the bifunctional molecule may comprise the steps of: (a) providing a target protein binding ligand (as defined herein); (b) linking (e.g.
  • the bifunctional molecule of the present invention may not comprise one or more structures.
  • the bifunctional molecule of the present invention does not comprise bifunctional molecules, or Z, having the structure of the disclaimer defined below.
  • Aryl/heteroaryl cyanoacrylamides In examples of the present invention, the bifunctional molecule of the first aspect does not comprise bifunctional molecules, or Z, having the structure of Disclaimer 2, as defined below.
  • the bifunctional molecule of the first aspect does not comprise a bifunctional molecule, or Z, having the general formula (DII): wherein R D1a is selected from C 1 to C 6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally wherein the C 1 to C 6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S and/or is substituted with a carbocyclic or heterocyclic group; A is absent or is CR D2a R D2a’ ; ring E is selected from aryl, heteroaryl, substituted aryl and substituted heteroaryl; R D2a and R D2a’ are each independently selected from H and C 1 to C 6 alkyl, optionally wherein the C 1 to C 6 alkyl is substituted with one or more heteroatoms selected from N, O or S, or wherein R 2 and R 2’ together
  • groups R D4a and A may be held at adjacent positions on the aryl, heteroaryl, substituted aryl or substituted heteroaryl ring.
  • the R D4a and A groups may be in a 1,2-substitution pattern with one another, or may be separated by 3 bonds.
  • ring E is a heteroaryl or substituted heteroaryl
  • a heteroatom contained within ring E may be directly bonded to A or R D4a .
  • the linker is appended to moiety Z via ring E.
  • the linker may be attached to moiety Z by way of a covalent bond between an atom on the linker and an atom contained in the ring system of the optionally substituted aryl or heteroaryl group of ring E.
  • This linker may be attached to ring E at any position on the optionally substituted aromatic or heteroaromatic ring (provided it has the correct valency and/or is chemically suitable).
  • the linker may replace a hydrogen atom at any position on the aromatic or heteroaromatic ring.
  • the bifunctional molecule, or Z, to be disclaimed may comprise a structure as shown in formula (DII) above, wherein: A, ring E, X and R D4a are as defined above; and wherein R D1a is selected from optionally substituted C 1 to C 6 alkyl, optionally substituted C 1 to C 6 haloalkyl, optionally substituted benzyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; R D2a and R D2a’ are each independently selected from H and optionally substituted C 1 to C 6 alkyl, or wherein R D2a and R D3a’ together form a 3-, 4-, 5- or 6-membered optionally substituted carbocyclic or heterocyclic ring; and R D3a is selected from optionally substituted C 1 to C 6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl and optionally substituted heterocyclyl.
  • R D1a is selected
  • Z to be disclaimed may be represented by formula (DIIa): wherein A, B, R 3 , X and LII are as defined for formula (DII); and n is 1, 2 or 3; W is selected from CR W1 R W2 , O, NR W3 , and S; and R W1 , R W2 and R W3 are each independently selected from H and C 1 to C 6 alkyl; and wherein when n is 2 or 3, each W is independently selected from CR W1 R W2 , O, NR W3 , and S.
  • ring E, R D2a’ , R D3a , R D4a , X and LII are as defined for formula (DII); m is 3, 4 or 5; each T is independently selected from CR T1 R T2 , O, NR T3 , and S; and R T1 , R T2 and R T3 are each independently selected from H and C 1 to C 6 alkyl.
  • Z in those cases where R D2a and R D4a together form a 5-, 6- , or 7- membered heterocyclic or carbocyclic ring, Z may be represented as formula (DIIc): wherein ring E, R D1a , R D2a’ , R D3a , X and LII are as defined for formula (I); p is 2, 3 or 4; and each U is independently selected from CR U1 R U2 , O, NR U3 , and S; and R U1 , R U2 and R U3 are each independently selected from H and C 1 to C 6 alkyl.
  • the bifunctional molecule, or Z, to be disclaimed may comprise a structure according to formula (ZII):
  • R D1a is not H; A is absent or is CR D2a R D2a’ ; ring E is selected from aryl, heteroaryl, substituted aryl and substituted heteroaryl; wherein R D1a and R D4a are not joined to form a ring; or wherein R D1a and R D4a together form a 5-, 6-, or 7 –membered heterocyclic ring; or wherein when A is CR D2a R D2a’’ : R D1a and R D2a together form a 5-, 6-, or 7-membered heterocyclic ring; or R D2a and R D4a together form a 5-, 6-, or 7- membered heterocyclic or carbocyclic ring.
  • q1 is any integer between 1 and 20, or between 1 and 10 (e.g. between 1 and 5).
  • the linker is or comprises one or more of:
  • q2 is any integer between 1 and 20, or between 1 and 10 (e.g.3, 4, 6 or 10).
  • the structures shown above represent the entire linker.
  • the linker of the bifunctional molecule to be disclaimed may comprise a plurality of the structures shown above. In these structures, the wavy lines are shown over the bond(s) that forms the link with further portions of the linker, the TBL and Z moieties respectively.
  • aryl refers to a mono- or polycyclic aromatic hydrocarbon system having 6 to 14 carbon atoms, in some cases having 6 to 10 carbon atoms.
  • aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl.
  • substituted aryl refers to an aryl group as defined herein which comprises one or more substituents on the aromatic ring. When an aryl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • heteroaryl may be a single or fused ring system having one or more aromatic rings containing 1 or more, in some cases 1 to 3, in some cases 1 to 2, in some cases a single O, N and/or S heteroatom(s).
  • heteroaryl may refer to a mono- or polycyclic heteroaromatic system having 5 to 10 ring atoms.
  • heteroaryl groups may include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl etc.
  • substituted heteroaryl refers to a heteroaryl group as defined herein which comprises one or more substituents on the heteroaromatic ring.
  • alkyl refers to a straight or branched chain hydrocarbyl group.
  • the chain may be saturated or unsaturated, e.g. in some cases the chain may contain one or more double or triple bonds.
  • C 1 -C 6 alkyl refers to a straight or branched chain hydrocarbyl group containing from 1 to 6 carbon atoms.
  • a “C 1 -C 3 alkyl” refers to a straight or branched chain hydrocarbyl group containing from 1 to 3 carbon atoms.
  • any hydrogen atom(s), CH 3 ,CH 2 or CH group(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • a “cycloalkyl” is a ring containing 3 to 10 carbon atoms, in some cases 3 to 8, or in some cases 5 to 6 carbon atoms.
  • the ring may be saturated or unsaturated, e.g. in some cases the ring may contain one or more double or triple bonds.
  • a C 3 -C 7 cycloalkyl is a cycloalkyl containing 3 to 7 carbon atoms in the ring.
  • a C 3- C 6 cycloalkyl is a cycloalkyl containing 3 to 6 carbon atoms in the ring.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynl etc.
  • substituted cycloalkyl refers to a cycloalkyl group as defined herein which comprises one or more substituents on the cycloalkyl ring.
  • alkenyl defines monovalent groups derived from alkenes by removal of a hydrogen atom from any carbon atom, wherein the term “alkene” is intended to define acyclic branched or unbranched hydrocarbons having the general formula CnH 2n , wherein n is an integer ⁇ 2.
  • alkenyl groups include ethenyl, n-propylenyl, iso-propylenyl, n-butylenyl, sec- butylenyl, iso-butylenyl and tert-butylenyl.
  • any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • the alkenyl comprises a divalent hydrocarbon radical, this moiety may sometimes be referred to herein as an alkenylene.
  • alkynyl defines monovalent groups derived from alkynes by removal of a hydrogen atom from any carbon atom, wherein the term “alkyne” is intended to define acyclic branched or unbranched hydrocarbons having the general formula CnH 2n-2 , wherein n is an integer ⁇ 2.
  • alkynyl groups include ethynyl, n-propylynyl, iso-propylynyl, n-butylynyl, sec- butylynyl, iso-butylynyl and tert-butylynyl.
  • any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • the alkynyl comprises a divalent hydrocarbon radical, this moiety may sometimes be referred to herein as an alkynylene.
  • Benzyl as used herein refers to a -CH 2 Ph group.
  • a “substituted benzyl” refers to a benzyl group as defined herein which comprises one or more substituents on the aromatic ring.
  • any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • heterocycloalkyl refers to a monocyclic or polycyclic ring having in one or more rings of the ring system at least one heteroatom selected from O, N and S (e.g. from one to five ring heteroatoms independently selected from the group consisting of O, N and S).
  • the one or more rings may also contain one or more double bonds provided that the one or more rings are not fully aromaticized.
  • the one or more rings of the heterocycloalkyl may comprise 3 to 10 atoms, in some cases 3 to 8 atoms.
  • the one or more rings may be aliphatic.
  • the one or more rings may be saturated or unsaturated, e.g. in some cases the one or more rings may contain one or more double or triple bonds.
  • any N heteroatom present in the heterocycloalkyl group may be C 1 to C6 alkyl-substituted.
  • the heterocycloalkyl is a monocyclic or bicyclic ring, such as a monocyclic ring.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, morpholinyl, dioxanyl, oxazolidinyl, tetrahydropyranyl, diazaspiroundecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, etc.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group as defined herein which comprises one or more substituents on the heterocycloalkyl ring.
  • -CH(aryl)-, –CH(substituted aryl)-, -CH(heteroaryl)- and –CH(substituted heteroaryl) refers to a methylene moiety that comprises an aryl, substituted aryl, heteroaryl or substituted heteroarylsubstituent and is the attachment point for the linker L.
  • heterocyclyl refers to a monovalent radical derived from a heterocycle.
  • a heterocycle is a cyclic compound (a compound comprising one or more rings of connected atoms) having as ring members atoms of at least two different elements (such as carbon and nitrogen).
  • a “carbocyclic ring” is a ring containing 3 to 10 carbon atoms, in some cases 3 to 8 carbon atoms, or in some cases 5 to 6 carbon atoms.
  • the ring may be aliphatic.
  • references to “carbocyclyl” and “substituted carbocyclyl” groups may refer to aliphatic carbocyclyl groups and aliphatic substituted carbocyclyl groups.
  • the ring may be saturated or unsaturated, e.g.
  • the ring may contain one or more double or triple bonds.
  • Representative examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynl etc.
  • substituted carbocyclyl refers to a carbocyclyl group as defined herein which comprises one or more substituents on the carbocyclic ring.
  • any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.
  • a “heterocyclic ring” (or heterocyclyl) may comprise at least 1 heteroatom selected from O, N and S.
  • the heterocyclic ring may be a monocyclic or polycyclic ring, each ring comprising 3 to 10 atoms, in some cases 3 to 8 atoms.
  • the one or more rings may be aliphatic.
  • references to “heterocyclyl” and “substituted heterocyclyl” groups may refer to aliphatic heterocyclyl groups and aliphatic substituted heterocyclyl groups.
  • the one or more rings may be saturated or unsaturated, e.g. in some cases the one or more rings may contain one or more double or triple bonds. Any N heteroatom present in the heterocyclic group may be C 1 to C6 alkyl-substituted.
  • the heterocyclyl is a monocyclic or bicyclic ring, such as a monocyclic ring. In other examples, the heterocyclyl may be a bicyclic ring, which may, in some cases be a fused ring.
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, morpholinyl, dioxanyl, oxazolidinyl, tetrahydropyranyl, diazaspiroundecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, pyrrolizidinyl, etc.
  • substituted heterocyclyl refers to a heterocyclyl group as defined herein which comprises one or more substituents on the heterocyclic ring.
  • a group comprising carbon atoms is defined as “saturated”, only single bonds bind the carbon atoms to one another.
  • a group comprising carbon atoms is defined as “unsaturated”, at least two of the carbon atoms are connected by a double or triple bond.
  • unsaturated compounds may comprise any number of double and/or triple bonds, provided that “Cycloalkene” is used herein to refer to an unsaturated monocyclic hydrocarbon having one endocyclic double bond.
  • spiro is used to refer to moieties comprising two or more ring systems, wherein at least two of the ring systems are connected by just one atom (typically a quaternary carbon atom).
  • “Monocyclic” is used herein to refer to moieties comprising one ring of atoms.
  • Bicyclic is used herein to refer to moietes that feature two joined rings of atoms.
  • Tricyclic is used herein to refer to moieties that feature three joined rings of atoms.
  • Polycyclic is used herein to refer to moieties that comprise two or more joined rings. Unless the context indicates otherwise, bicyclic and polycyclic systems may comprise a fused ring system (in which at least two rings share a common bond).
  • the two or more rings may be joined by a bond between atoms on each of the two or more rings.
  • the bicyclic system may comprise a spiro centre (as defined above).
  • bridged is used herein to refer to a cyclic compound, or ring, comprising two bridgehead atoms (typically two carbon atoms of the cyclic compound or ring) that are connected by one or more atoms lying outside of the ring (such as one to three atoms lying outside of the ring).
  • Bridged rings comprise two rings sharing three or more atoms.
  • the bridgehead atoms are separated within the ring by at least one carbon atom.
  • a ring may be bridged by between 1 and 3 bridging atoms which lie outside of the ring to form a bridging group (optionally wherein the bridging atoms are selected from C, N, O and S).
  • a “C 1-3 bridge” is a bridging group comprising between 1 and 3 carbon bridging atoms.
  • the bridging group may compirise one to three atoms lying outside of the ring, of which one, two or three of those atoms are carbon.
  • the bridging group may additionally comprise non-carbon atoms (such as a heteroatom selected from N, O and S).
  • a “C 1-3 bridge” may refer to a bridging group comprising between 1 and 3 atoms of which one, two or three are carbon and the remainder (if any) are selected from N, O and S.
  • the bridging group may be a C 1 to C 3 alkylene (such as methylene, ethylene or propylene).
  • the C 1 to C 3 alkylene bridging group may be optionally substituted with any suitable substituent as described herein.
  • C 1 to C 3 alkylene bridging group may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl and C 1 to C 3 alkoxy.
  • fused is used to refer to moieties comprising two or more ring systems, wherein at least two of the ring systems are connected by a [1,2] ring junction, i.e. a moiety comprising two or more ring systems wherein two, or more, of the rings present share a bond in each respective ring structure.
  • aliphatic refers to acyclic or cyclic, saturated or unsaturated compounds, excluding aromatic compounds, where “aromatic” defines a cyclically conjugated molecular entity with a stability (due to delocalisation) significantly greater than that of a hypothetical localised structure.
  • the Hückel rule is often used in the art to assess aromatic character; monocyclic planar (or almost planar) systems of trigonally (or sometimes digonally) hybridised atoms that contain (4n+2) ⁇ -electrons (where n is a non-negative integer) will exhibit aromatic character.
  • hydrocarbyl refers to a monovalent radical derived from a hydrocarbon by the removal of a hydrogen atom from the hydrocarbon.
  • a hydrocarbon is any molecule comprising only the elements carbon and hydrogen. Hydrocarbons may be aliphatic, aromatic, unsaturated or saturated.
  • an alkoxy refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-.
  • a C 1-4 alkoxy refers to a C 1-4 alkyl group (as defined above), appended to the parent molecular moiety through a oxy group, -O- .
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.
  • alkoxyalkyl may refer to a moiety derived from an alkyl moiety in which a hydrogen atom at any position of the alkyl is substituted with an alkoxy moiety.
  • alkoxyalkyl groups include methoxyethyl, methoxypropyl, ethoxymethyl and the like.
  • alkylcarbonyl refers to carbonyl having alkyl mentioned above.
  • alkylcarbonyl examples include C 1-6 alkylcarbonyl (-C(O)C 1-6 alkyl), such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert- butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, with methylcarbonyl being preferable.
  • C 1-6 alkylcarbonyl such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert- butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, with methylcarbonyl being preferable.
  • alkylamino is used herein to refer to a moiety derived from an amino (NH 2 ) moiety in which one or both hydrogen atom(s) of the amino is/are substituted with one or two alkyl moieties.
  • alkylamino groups include dimethylamino, diethylamino and the like.
  • alkylcarbonylaminoalkyl refers to aminoalkyl having alkylcarbonyl mentioned above.
  • alkylcarbonylaminoalkyl include C 1-6 alkylcarbonylaminoalkyl, such as methylcarbonylaminomethyl and ethylcarbonylaminomethyl.
  • alkylaminocarbonyl refers to carbonyl having at least one alkylamino group.
  • alkylaminocarbonyl include C 1-6 alkylamino-C 1-6 alkyl, such as methylaminocarbonyl, and ethylaminocarbonyl.
  • alkylaminoalkyl refers to alkyl mentioned above having at least one alkylamino group mentioned above.
  • alkylaminoalkyl include C 1-6 alkylamino-C 1- 6 alkyl, such as methylaminomethyl, methylaminoethyl, ethylaminomethyl, and ethylaminopropyl.
  • alkoxyalkylene is used herein to refer to a moiety derived from an alkylene moiety in which a hydrogen atom at any position of the alkylene is substituted with an alkoxy moiety.
  • alkoxyalkylene groups include methoxyethylene, methoxymethylene and the like.
  • haloalkylene is used herein to refer to a moiety derived from an alkylene moiety in which one or more hydrogen atom(s) at any position(s) of the alkylene is/are substituted with one or more halo moieties.
  • haloalkylene groups include fluoroethylene, difluoromethoxymethylene, dichloroethylene and the like.
  • hydroxyalkylene is used herein to refer to a moiety derived from an alkylene moiety in which a hydrogen atom at any position of the alkylene is substituted a hydroxy moiety.
  • hydroxyalkylene groups include hydroxyethylene, hydroxymethylene and the like.
  • cycloalkoxy is used herein to refer to a moiety derived from a linear alkoxy moiety in which a bond forms between the oxygen atom of the OH moiety and the carbon atom at the end of the alkyl chain (by abstraction of the hydrogen atom of the OH moiety and a hydrogen atom at the end of the alkyl chain).
  • cycloalkoxy groups examples include oxacyclohexanyl, oxacyclopentanyl and the like.
  • the term “carbocyclylamino” is used herein to refer to a moiety derived from an linear monohydrocarbylamino moiety in which a bond forms between the nitrogen atom of the NH moiety and the carbon atom at the end of the hydrocarbyl chain (by abstraction of the hydrogen atom of the NH moiety and a hydrogen atom at the end of the hydrocarbyl chain).
  • Examples of carbocyclylamino groups include piperidinyl, pyrrolidinyl, pyridinyl, pyrrolyl and the like.
  • substituted means that the moiety comprises one or more substituents.
  • optionally substituted means that the moiety may comprise one or more substituents.
  • a “substituent” may include, but is not limited to, hydroxy, thiol, carboxyl, cyano (CN), nitro (NO 2 ), halo, haloalkyl (e.g. a C 1 to C 6 haloalkyl or a C 1 to C 4 haloalkyl), an alkyl group (e.g. C 1 to C 10 or C 1 to C 6 ), an alkenyl group (e.g.
  • alkynyl group e.g. C 2 to C 6
  • aryl e.g. phenyl and substituted phenyl for example benzyl or benzoyl
  • morpholino N- C 1-6 alkylenylmorpholine
  • alkoxy group e.g. C 1 to C 6 alkoxy or C 1 to C 4 alkoxy
  • haloalkoxy e.g. C 1 to C 4 haloalkoxy
  • aryloxy e.g. phenoxy and substituted phenoxy
  • hydroxyalkynyl e.g. C 2 to C 6
  • thioether e.g.
  • C 1 to C 6 alkyl or aryl thioether examples include alkylthio (e.g. C 1 to C 6 alkylthio), cyanoalkyl (e.g. C 1 to C 6 ), oxo, keto (e.g. C 1 to C 6 keto), ester (e.g. C 1 to C 6 alkyl or aryl ester, which may be present as an oxyester or carbonylester on the substituted moiety), thioester (e.g.
  • alkylene ester such that attachment is on the alkylene group, rather than at the ester function which is optionally substituted with a C 1 to C 6 alkyl or aryl group
  • amine including monoalkylamino, dialkylamino, a five- or six-membered cyclic alkylene amine optionally substituted with one or more halo, further including a C 1 to C6 alkyl amine or a C 1 to C 6 dialkyl amine which alkyl groups may be substituted with one or two hydroxyl groups, and also including alkylphenylamino or alkylphenyl(alkyl)amino groups), amido (including –C(O)NH 2 , -C(O)NH(alkyl) such as -C(O)NH(C 1-4 alkyl), –C(O)N(alkyl) 2 such as –C(O)N(C 1-4 al
  • C 1 to C 6 alkyl groups including a carboxamide which is optionally substituted with one or two C 1 to C 6 alkyl groups
  • aminoalkyl e.g. C 1 to C 4 aminoalkyl
  • alkanol e.g. C 1 to C 6 alkyl, C 1 to C 4 alkyl or aryl alkanol
  • carboxylic acid e.g.
  • C 1 to C 6 alkyl or aryl carboxylic acid sulfoxide, sulfone, sulfinimide, sulfonamide, and urethane (such as -O-C(O)-NR 2 or–N(R)- C(O)-O-R, wherein each R in this context is independently selected from C 1 to C 6 alkyl or aryl), a heteroaryl, arylalkyl (such as an arylC 1-4 alkyl), heteroarylalkyl (such as a heteroarylC 1-4 alkyl), -OC 1-4 alkylphenyl, -C(O)alkyl such as –C(O)(C 1-4 alkyl), -C(O)alkylphenyl such as C(O)(C 1- 4 alkylphenyl), -C(O)haloalkyl such as –C(O)( C1-4 haloalkyl), -SO 2 (alkyl) such as
  • a “substituent” may include, but is not limited to, halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy.
  • a “halo” group may be F, Cl, Br, or I. In some examples, halo may be F.
  • haloalkyl may be an alkyl group in which one or more hydrogen atoms thereon have been replaced with a halogen atom, e.g.
  • a C 1 -C 6 haloalkyl may be a C 1 to C 6 alkyl in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • a C 1-C6 haloalkyl may be a fluoroalkyl, such as trifluoromethyl (–CF 3 ) or 1,1-difluoroethyl (-CH 2 CHF 2 ).
  • a cyclohaloalkyl refers to a cycloalkyl as defined above, in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • a “C 3 to C 7 cyclohaloalkyl” refers to a C 3 to C 7 cycloalkyl in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • a “C 1-4 haloalkoxy” refers to a C 1-4 alkoxy as defined above, in which one or more hydrogen atoms thereon have been replaced with a halogen atom.
  • aryl As used herein, the terms “aryl”, “substituted aryl”, “heteroaryl”, “substituted heteroaryl”, “cycloalkyl”, “C 1 to C 6 alkyl”, “heterocycloalkyl”, and “substituted heterocycloalkyl” may refer to either a monovalent radical species or a divalent radical species.
  • R 1 is typically a monovalent group that is attached to the heterocyclic core of Z and so the terms aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C 1 to C 6 alkyl should be understood to represent a monovalent radical moiety.
  • R 2 for Z is typically a divalent group that is covalently attached to both the heterocyclic core of Z and also the linker.
  • aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl should be understood to represent divalent radical moiety.
  • the terms “comprise”, “comprising” and/or “comprises” is/are used to denote that aspects, embodiments and examples of this disclosure “comprise” a particular feature or features. It should be understood that this/these terms may also encompass aspects, embodiments and/or examples which “consist essentially of” or “consist of” the relevant feature or features.
  • LC-MS Liquid Chromatography Mass Spectra
  • ESI + positive ion electron spray ionisation
  • Agilent InfinityLab Single Quadrupole LC/MSD with a Waters XBridge® C183.5 ⁇ m column (2.1mm ⁇ 50mm) using H 2 O+MeCN (5-95%) + 0.1% HCO 2 H or H 2 O+MeCN (20-95%) + 0.1% HCO 2 H as eluent, using a linear gradient over 3 minutes.
  • Example 1a tert-butyl (5-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4- tetrahydroquinolin-6-yl)benzamido)pentyl)carbamate: (see scheme 1) To a stirred solution of commercially available GSK1324726A (1.1 equiv., 5.9 g, 13.6 mmol) in DMF (25 ml) were added DIPEA (3 equiv., 4.79 g, 6.4577 mL, 37.075 mmol) and HATU (1.1 equiv., 5.17 g, 13.6 mmol) at 0 °C and stirred for 10 min.
  • GSK1324726A 1.1 equiv., 5.9 g, 13.6 mmol
  • DIPEA 3 equiv., 4.79 g, 6.4577 mL, 37.075 mmol
  • Example 2a 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4- tetrahydroquinolin-6-yl)-N-(5-aminopentyl)benzamide hydrochloride: (see scheme 1) To a stirred solution of tert-butyl (5-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl- 1,2,3,4-tetrahydroquinolin-6-yl)benzamido)pentyl)carbamate (1a) (4.5 g, 7.27 mmol) in DCM (100 ml) was added HCl (4M in dioxane) (18.
  • Example 3 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4- tetrahydroquinolin-6-yl)-N-(1-chloro-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosan-20- yl)benzamide (see scheme 3)
  • reaction was allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by LC-MS. After completion, the reaction was quenched by addition of NH 4 Cl (saturated aqueous solution) the mixture was extracted with DCM (10 mL). The organic phase was dried over MgSO 4 and concentrated under reduced pressure.
  • NH 4 Cl saturated aqueous solution
  • Example 6a N-(5-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4- tetrahydroquinolin-6-yl)benzamido)pentyl)-5-(m-tolyl)piperidine-3-carboxamide hydrochloride (see for example, scheme 3)
  • Example 7a N-(5-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4- tetrahydroquinolin-6-yl)benzamido)pentyl)-1-(2-cyanoacetyl)-5-(m-tolyl)piperidine-3- carboxamide (see, for example, scheme 2)
  • N-(5-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4- tetrahydroquinolin-6-yl)benzamido)pentyl)-5-(m-tolyl)piperidine-3-carboxamide hydrochloride (6a) (1 equiv., 31.5 mg, 0.0416 mmol) in 1,4-di
  • Example 9a 5-phenylnicotinic acid To a stirred solution of 5-bromonicotinic acid (1.0 equiv., 2.0 g, 9.90 mmol), phenylboronic acid (1.2 equiv., 1.4 g, 11.88 mmol) in Dioxane (20 ml) H 2 O (4.0 ml) was added K 2 CO 3 (2.0 equiv., 2.7 g, 19.80 mmol). After addition the reaction mixture was degassed with N 2 gas for 20 min and then added catalyst Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (0.1 equiv., 0.80 g, 0.990 mmol) at RT and then stirred at 100 O C for 16 h.
  • Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 0.1 equiv., 0.80 g, 0.990 mmol
  • Example 10a 5-phenylpiperidine-3-carboxylic acid (see, for example, scheme 5) To a stirred solution of 5-phenylnicotinic acid (1.0 equiv., 0.500 g, 2.510 mmol) in acetic acid (20 ml) was added Platinum(IV) oxide (0.4 equiv., 0.285 g, 1.255 mmol) at room temperature and stirred under hydrogen gas bladder pressure for 48 h. The progress of the reaction was monitored by LCMS. Reaction mass was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure.
  • N.B.3–piperidine carboxylic acid is commercially available and, for example, can be obtained from Sigma-Aldrich.
  • Compounds 10a to 10k and 3-piperidine carboxylic acid are then reacted with DIPEA and 1- cyanoacetyl-3,5-dimethyl-1H-pyrazole (as illustrated in step iii, scheme 5).
  • Piperidine –pyrrolidine­based warheads Further examples of bifunctional degraders comprising a piperidine- pyrrolidine-based moiety as Z are illustrated below. Overviews of various exemplary synthetic methods that may be used to provide these compounds are shown below. Overview of synthetic pathway – scheme 7 Overview of synthetic pathway – scheme 8
  • bifunctional compounds Synthesis of the final bifunctional degraders is illustrated in scheme 8. Cyanoacrylamide acids and amine-linker functionalised target protein binding ligand are dissolved in DMF and treated with HATU and DIPEA at room temperature to afford the bifunctional compounds. An example compound that are made in accordance with the method illustrated in scheme 8 are shown below. Pyrrolidine­based warheads Further examples of bifunctional degraders comprising a pyrrolidine-based moiety as Z are illustrated below. Overviews of various exemplary synthetic methods that may be used to provide these compounds are shown below. Overview of synthetic pathway – scheme 9 Overview of synthetic pathway – scheme 10
  • reaction mixture was monitored by TLC.
  • the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (100 mL ⁇ 2). Combined organic layer was washed with brine solution (50 mL), dried over Na 2 SO 4 and filtered, concentrated under vacuum.
  • the crude residue was purified by flash column chromatography, using 0 to 10% ethyl acetate in hexane to afford pure product ethyl 1-benzyl-4-(m-tolyl)pyrrolidine-3- carboxylate (8 g, 24.49 mmol, 93 % yield) as a pale yellow liquid.
  • Step-4 Synthesis of ethyl 1-(2-cyanoacetyl)-4-(m-tolyl)pyrrolidine-3-carboxylate: To a stirred solution of ethyl 4-(m-tolyl)pyrrolidine-3-carboxylate (100 mg, 0.429 mmol) in Acetonitrile (2 mL) were added DIPEA (0.150 mL, 0.857 mmol), 3-(3,5-dimethyl-1H-pyrazol- 1-yl)-3-oxopropanenitrile (84 mg, 0.514 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 3 h under N 2 atmosphere. The progress of reaction mixture was monitored by TLC.
  • reaction mixture was diluted with water (2 mL), extracted with ethyl acetate (10 mL ⁇ 2). Combined organic layer was dried over Na 2 SO 4 and filtered, and concentrated under vacuum. The crude residue was purified by flash column using 0 to 20% ethyl acetate in hexanes to afford the product ethyl 1-(2-cyanoacetyl)-4-(m-tolyl)pyrrolidine-3-carboxylate (90 mg, 0.191 mmol, 44.7 % yield) as a yellow semi-solid.
  • bifunctional compounds Synthesis of the final bifunctional degraders is illustrated in scheme 10. Cyanoacrylamide acids and amine-linker functionalised target protein binding ligand are dissolved in DMF and treated with HATU and DIPEA at room temperature to afford the bifunctional compounds. Example compounds that are made in accordance with the method illustrated in scheme 10 are shown below.
  • Boc Deprotection – General Procedure 2a A solution of Boc protected amine (I) (1.0 equiv.) in CH 2 Cl 2 (0.05 M) was treated with HCl (4 M in dioxane, 50 equiv.) and the mixture was stirred for 2 h. The volatiles were evaporated in vacuo to yield the corresponding amine hydrochloride (II). Amide coupling – General procedure 3a To a stirred solution of carboxylic acid (I) (1.5 equiv.) in DMF was added DIPEA (2.5 equiv.) and HATU (1.5 equiv.).
  • Table 2a The following examples were prepared following general procedure 2a using the starting materials synthesized in Table 1a.
  • Table 3a The following examples were prepared following general procedure 3a using starting materials synthesized in Table 2a and (E/Z)-2-cyano-4,4-dimethylpent-2-enoic acid.
  • Table 4a The following examples were prepared following general procedure 4a using starting materials synthesized in Table 2a.
  • Table 5a The following examples were prepared following general procedure 5a using starting materials synthesized in Table 4a.
  • Table 6a The following examples were prepared following general procedure 7a using starting materials synthesized in Table 4a.
  • Table 7a The following examples were prepared following general procedure 8a using starting materials synthesized in Table 4a.
  • Table 8a The following examples were prepared following general procedure 6a using starting materials synthesized in Table 4a.
  • Table 9a The following examples were prepared following general procedure 3a using carboxylic acid synthesized according to WO 2021/178920 (compound B11-1, page 316) and amine specified in Table 9a.
  • Table 11a The following examples were prepared following general procedure 3a using starting materials synthesized in Table 10a and (E/Z)-2-cyano-4,4-dimethylpent-2-enoic acid.
  • BRD9w 7­bromo­5­methylthieno[3,2­c]pyridin­4(5H)­one
  • K 2 CO 3 6.01 g, 43.5 mmol
  • Table 12a The following exemplary compounds were prepared by General Procedure 3b using 5-(3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl)-1,3,4-trimethylpyridin-2(1H)-one synthesized in Table 2a and the appropriate acid selected from Pipacid 0 to 39 and Pyracid 0 to 47 as defined above..
  • SMARCA2/SMARCA4 degraders Protein degrading compounds that have an E3 ligase binding portion and a SMARCA2 or SMARCA4 binding portion wherein the SMARCA2 or SMARCA4 binding ligand binds to SMARCA2 or SMARCA4 and brings it to the ligase for ultimate degradation by the proteasome are described in WO 2021/155321 A2, WO 2021/207291 A1, WO 2021/142247 A1, WO 2021/133920 A1, WO 2020/251972 A1, WO 2020/251971 A1, WO 2020/251969 A1, WO 2020/010227 A1, WO 2021/083949 A1, WO 2021/086785 A1, WO 2021/067606 A1, WO 2019/207538 A1, WO 2020/078933 A1, US 20200038378 A1, and WO 2019/195201 A1.
  • reaction mixture was heated to 130 o C and stirred for 12 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was extracted with ethyl acetate (250 mL x 2) and water (100 mL x 2). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4 g, crude) as an off white solid.
  • the reaction mixture was degassed with argon for 20 min, and then Pd(dppf)Cl 2 .DCM (0.12 g, 0.15 mmol) was added at the same temperature.
  • the reaction mixture was heated to 100 o C and stirred for 16 h.
  • the reaction was monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate (250 mL x 2) and diluted with water (100 mL x 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by medium pressure liquid chromatography, eluted with 5% methanol in DCM to afford 2-(6-amino-5-(3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)-4-fluorophenol (0.12 g, 70%) as an off white solid.
  • reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with ammonium chloride solution then extracted with ethyl acetate (200 mL x 2) and diluted with water (100 mL). Combined organic layer was dried over sodium sulfatesulfate and concentrated under reduced pressure to afford tert-butyl 4-(1-hydroxyethyl)piperidine-1-carboxylate (20 g, quantitative yield) as brown liquid. LC-MS: 406.2 (M+H)+; 99.16% at RT: 1.59 min.
  • reaction mixture was heated to 70 o C and stirred for 18 h. The reaction was monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate (250 mL x 2) and water (100 mL x 2). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was degassed for 30 min, and then Pd(dppf)Cl 2 .DCM (0.36 g, 0.49 mmol) was added at the same temperature.
  • the reaction mixture was heated to 110 o C and stirred for 5 h.
  • the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 10% methanol in DCM then concentrated under reduced pressure.
  • reaction mixture was degassed for 30 min, and then tetrakis (0.25 g, 0.22 mmol) was added at the same temperature.
  • the reaction mixture was heated to 100 o C and stirred for 12 h.
  • the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 10% methanol in DCM then concentrated under reduced pressure.
  • reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was concentrated under reduced pressure. The crude product was purified by medium pressure liquid chromatography, eluted with 20%EtoAc in heptane to afford di-tert-butyl 3-chloro-7,8-dihydro- 5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate (0.3 g, 30.62%) as an off white solid.
  • reaction mixture was degassed for 10 min, and then Pd(dppf)Cl 2 .DCM (30.2 mg, 0.037 mmol) was added.
  • the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate (15 mL x 2). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • reaction mixture was allowed to warm to room temperature and stirred for 16 h.
  • the reaction was monitored by TLC; after completion, the reaction mixture was diluted with water and extracted with DCM. Combined organic layer was separated and aqueous layer was washed with DCM. Organic layer was distilled and concentrated under reduced pressure.
  • the crude product was purified by medium pressure liquid chromatography, eluted with 70-80% ethyl acetate to afford tert-butyl (E)-2-(4- (2-cyano-4,4-dimethylpent-2-enoyl)piperazin-1-yl)acetate (0.3 g, 44 %) as pale yellow solid.
  • Table 2b The following table indicates the intermediates used to prepare the indicated examples, following general procedure 1b.
  • Example 1 – BET (BRD4) degradation 1.1 Assay 1 ­ Degradation of HiBit­BRD4 in HEK293 HEK293 containing a HiBit insertion for BRD4 were plated in 384-well tissue culture plates at a density of 8 x 10 4 per well in a volume of 36 ⁇ L and incubated overnight at 37 o C and 5% CO 2 . Wells were treated with test compounds for 6 h prior to addition of the NanoLuc substrate and reading on a ClarioSLARIOstar Plus. Degradation data was plotted and analysed using Prism 86 (Graphpad). The degradation of target protein BRD4 was detected according to the procedure outlined in assay 1 (Degradation of HiBit-BRD4 in HEK293) for the following compounds.
  • Table 1.1 shows the bifunctional molecules that were analysed in accordance with the procedure outlined in assay 1.
  • the DC 50 values for all of the compounds shown in Table 1.1 were all found to be less than or equal to 1000 nM. These molecules were all considered to be effective degraders.
  • the DC 50 values for compounds 8a, 8b, 8e, 8f, 8g, and 8h was found to be less than 500 nM. These molecules were considered to be particularly effective degraders.
  • Example 2 BRD9 degradation Assay Protocol 1 ­ Degradation of HiBit­BRD9 in HEK293 HEK293 stably expressing LgBit and containing a HiBit insertion for BRD9 were plated in 384- well tissue culture plates at a density of 8 x 10 3 per well in a volume of 36 ⁇ L and incubated overnight at 37 °C and 5% CO 2 . Wells were treated with test compounds (11 pt titration up to 10 ⁇ M) for 6 h prior to addition of Nano-Glo® Hibit Lytic buffer (1:50 substrate and 1:100 LgBit protein) and reading on a PheraSTAR. Degradation data was plotted and analysed using Prism 8 (Graphpad).
  • Wells were washed twice with DPBS then incubated with 25 ⁇ L of 1% BSA containing a 1:1000 dilution of Anti-rabbit Alexa FluorTM 647 secondary antibody (Thermo Scientific A21244) and 1 ⁇ g/mL Hoechst nuclear counter stain (Abcam ab228551) for 1 hour.
  • Wells were washed twice with DPBS prior to imaging on a Perkin Elmer Operetta CLS with 10X air lens. Images were processed using Harmony High-Content Imaging and Analysis Software (Perkin Elmer) and the mean contrast ratio of Alexa FluorTM 647 in central nuclei was used to quantify BRD9 protein levels.
  • Example 3 SMARCA2 degradation The bifunctional compounds were assayed to investigate their ability to degrade target proteins in accordance with the following general procedures.
  • Assay Protocol 1 HeLa cells with a HiBiT tag knocked in at the 3’ end of SMARCA2 were purchased from Promega (Custom product) (1). HeLa SMARCA2 HiBiT transfected cells were treated with compounds at indicated concentrations using the FlexDrop IQ (Perkin Elmer).24 hours after compound additions abundance of HiBiT tagged protein was quantified using NanoGlo HiBiT lytic detection system (Promega, N3050). Cell viability was measured using Cell Titre Glow cell viability assay (Promega, G9243).

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Abstract

La présente invention concerne une nouvelle classe de molécules bifonctionnelles qui sont utiles dans une dégradation ciblée ou sélective d'une protéine.
PCT/GB2023/051592 2022-06-16 2023-06-16 Molécules bifonctionnelles pour la dégradation ciblée de protéines WO2023242597A1 (fr)

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